Triazole and imidazole compounds and their use as antifungal therapeutic agents

ABSTRACT

The present invention provides an azole compound represented by the formula (I): ##STR1## wherein Ar is an optionally-substituted phenyl group; R 1  and R 2  are, the same or different, a hydrogen atom or a lower alkyl group, or R 1  and R 2  may combine together to form a lower alkylene group; R 3  is a hydrogen atom or an acyl group; Y is a nitrogen atom or a methine group; and A is an optionally-substituted saturated cyclic amide group bonded through a first nitrogen atom, or a salt thereof, which is useful for prevention and therapy of fungal infections of mammals as antifungal agent.

DESCRIPTION OF THE PRESENT INVENTION

1. Field of the Invention

The present invention relates to azole compounds which are useful as anantifungal therapeutic agent and a method of manufacturing the same aswell as the use thereof.

2. Prior Art

Various azole compounds exhibiting antifungal activity have beenreported (for example, EP0122056A1, EP0332387A1 and EP0122693A1).

However, these azole compounds are not satisfactory as pharmaceuticalagents in terms of antifungal activity, antifungal spectrum, adversereaction and the pharmacokinetics.

There has been a demand for the compounds which exhibit higher safety,better absorption in vivo and higher antifungal activity as anantifungal therapeutic agent.

SUMMARY OF THE INVENTION

The present invention relates to:

(1) a compound represented by the formula (I): ##STR2## wherein Ar is anoptionally-substituted phenyl group; R¹ and R² are, the same ordifferent, a hydrogen atom or a lower alkyl group, or R¹ and R² maycombine together to form a lower alkylene group; R³ is a hydrogen atomor an acyl group; Y is a nitrogen atom or a methine group; and A is anoptionally-substituted saturated cyclic amide group bonded through afirst nitrogen atom, or a salt thereof,

(2) a compound described in (1) above in which one of R¹ and R² is ahydrogen atom and another is a lower alkyl group,

(3) a compound described in (1) above in which Y is a nitrogen atom,

(4) a compound described in (1) above in which Ar is ahalogen-substituted phenyl group,

(5) a compound described in (4) above in which Ar is a phenyl groupsubstituted with 1 or 2 fluorine atoms,

(6) a compound described in (1) above in which A is a five- orsix-membered saturated cyclic amide group,

(7) a compound described in (1) above in which A is a saturated cyclicamide group having a second nitrogen atom in the ring,

(8) a compound described in (7) above in which the second nitrogen atomof the saturated cyclic amide group is attached to a substituent,

(9) a compound described in (1) above in which A is a 3-substitutedphenyl-2-oxo-1-imidazolidinyl group of the formula: ##STR3## wherein R⁴is a substituted phenyl group, (10) a compound described in (1) above inwhich A is a 4-substituted phenyl-2,5-dioxo-1-piperazinyl group of theformula: ##STR4## wherein R⁵ has the same meaning of R⁴. (11) a compounddescribed in (1) above in which A is a saturated cyclic amide groupsubstituted with a substituted phenyl group having 1 or 2 substituentsselected from the group consisting of a halogen atom, a halogenated C₁₋₆alkyl group and a halogenated C₁₋₆ alkoxy group,

(12) a compound described in (11) above in which the substituent of thesubstituted phenyl group is a fluorine atom, a fluorinated lower alkylgroup or a fluorinated lower alkoxy group,

(13) a process for preparing a compound of the formula (I) described in(1) above or a salt thereof which comprises reacting a compoundrepresented by the formula (II): ##STR5## wherein Ar is anoptionally-substituted phenyl group; R¹, and R² are, the same ordifferent, a hydrogen atom or a lower alkyl group, or R¹ and R² maycombine together to form a lower alkylene group; and A is anoptionally-substituted saturated cyclic amide group bonded through afirst nitrogen atom,

with a compound represented by the formula (III): ##STR6## wherein Y isa nitrogen atom or a methine group, or a salt thereof to give a compoundof the formula (I) in which R³ is a hydrogen atom, if necessary followedby treating with an acylating agent to obtain a compound of the formula(I) in which R³ is an acyl group,

(14) a process for preparing a compound of the formula (I) described in(9) above or a salt thereof which comprises reducing a compoundrepresented by the formula (I'): ##STR7## wherein Ar is anoptionally-substituted phenyl group; R¹ and R² are, the same ordifferent, a hydrogen atom or a lower alkyl group, or R¹ and R² maycombine together to form a lower alkylene group; R³ is a hydrogen atomor an acyl group; Y is a nitrogen atom or a methine group; and A" is a3-substituted phenyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl group, or a saltthereof, and

(15) an antifungal agent which comprises a compound (I) described in (1)above or a pharmaceutically acceptable salt thereof, excipient and/orcarrier.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Examples of the substituents for the optionally-substituted phenyl grouprepresented by Ar in the formulae (I), (II) and (I') are a halogen (forexample, fluorine, chlorine, bromine or iodine), a halogenated lower(C₁₋₄) alkyl group, a halogenated lower (C₁₋₄) alkoxy group, a lower(C₁₋₄) alkylsulfonyl group and a halogenated lower (C₁₋₄) alkylsulfonylgroup. Preferably, the substituent is a halogen (for example, fluorine,chlorine, bromine or iodine) and, particularly preferably, it isfluorine. Numbers of the substituents are preferably from 1 to 3 and,more preferably, 1 or 2.

Examples of Ar are a halogenophenyl group, a halogenated lower (C₁₋₄)alkylphenyl group, a halogenated lower (C₁₋₄) alkoxyphenyl group, alower (C₁₋₄) alkylsulfonylphenyl group and a halogenated lower (C₁₋₄)alkylsulfonylphenyl group.

In the above, examples of the halogenophenyl groups are2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl,2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl and 4-bromophenyl.

Examples of the halogenated lower (C₁₋₄) alkylphenyl groups are4-trifluoromethylphenyl group and the like.

Examples of the halogenated lower (C₁₋₄) alkoxyphenyl groups are4-trifluoromethoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyland 4-(2,2,3,3,3-pentafluoropropoxy)phenyl.

Examples of the lower (C₁₋₄) alkylsulfonylphenyl groups are4-methanesulfonylphenyl and the like.

Examples of the halogenated lower (C₁₋₄) alkylsulfonylphenyl groups are4-(2,2,2-trifluoroethanesulfonyl)phenyl,4-(2,2,3,3-tetrafluoropropanesulfonyl)phenyl and4-(2,2,3,3,3-pentafluoropropanesulfonyl)phenyl.

Preferred Ar is a phenyl group which is substituted particularly with 1or 2 halogens such as 2,4-difluorophenyl, 2,4-dichlorophenyl,4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl and 4-bromophenyl and,among which 4-fluorophenyl, 2-fluorophenyl and 2,4-difluorophenyl areespecially preferred.

Examples of the lower alkyl groups represented by R¹ or R² in theformulae (I), (II) and (I') are straight chain or branched alkyl groupshaving 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl and, among which methyl ispreferred. Preferred combinations of R¹ and R² are hydrogen andhydrogen; hydrogen and methyl; or methyl and methyl. Examples of thelower alkylene groups formed by connection of R¹ and R² are straightlower (C₂₋₄) alkylene groups such as ethylene, propylene and butyleneand, among which ethylene is preferred.

Among them, it is preferable that one of R¹ and R² is a hydrogen atomand the other is a methyl group.

Examples of the acyl groups represented by R³ in the formulae (I) and(I') are acyl groups derived from organic carboxylic acids such as analkanoyl group, preferably that with 1-7 carbon atoms (e.g., formyl,acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl orheptanoyl), particularly preferably that with 1-3 carbon atoms; anarylcarbonyl group, preferably that with 7-15 carbon atoms (e.g.,benzoyl or naphthalenecarbonyl), particularly preferably that with 7-11carbon atoms; an alkoxycarbonyl group, preferably that with 2-7 carbonatoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl or tert-butoxycarbonyl), particularly preferably thatwith 2-4 carbon atoms; an aryloxycarbonyl group, preferably that with7-15 carbon atoms (e.g., phenoxycarbonyl), particularly preferably thatwith 7-11 carbon atoms; an aralkylcarbonyl group, preferably that with8-20 carbon atoms (e.g., benzylcarbonyl, phenethylcarbonyl,phenylpropylcarbonyl or naphthylethylcarbonyl), particularly preferablythat with 8-14 carbon atoms. Those may be substituted with suitable oneto three substituent(s). Examples of suitable substituents are anoptionally-halogenated lower alkyl group, an aryl group and a halogen.

Preferably, the above acyl groups are those which can be hydrolyzed invivo. Specific examples thereof are formyl, acetyl, benzoyl andbenzylcarbonyl.

The saturated cyclic amide group in the optionally-substituted saturatedcyclic amide group bonded through a nitrogen atom represented by A inthe formulae (I) and (II) is preferably a saturated heterocyclic groupwhich has one to three nitrogen atoms and may have one oxygen or sulfuratom in a ring represented by a formula: ##STR8##

The above-mentioned saturated cyclic amide groups are a four- toeight-membered cyclic groups and, preferably, a five- or six-memberedcyclic group. Examples of such saturated cyclic amide groups are2-oxo-1-imidazolidinyl, 5-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl,3-oxo-2-pyrazolidinyl, 2-oxo-1-piperazinyl, 2-oxo-1-piperidinyl,3-oxomorpholino and 2-oxo-1-perhydropyrimidinyl.

It is particularly preferred that the saturated cyclic amide group hastwo nitrogen atoms in the ring. Examples of such saturated cyclic amidegroups are 2-oxo-1-imidazolidinyl, 2-oxo-1-piperazinyl and2-oxo-1-perhydropyrimidinyl.

Examples of the substituents in the saturated cyclic amide grouprepresented by A are an oxo group, a halogen (for example, fluorine,chlorine, bromine or iodine), an aliphatic hydrocarbon group which maybe substituted, an aromatic hydrocarbon group which may be substitutedand an aromatic hetero cyclic group which may be substituted. The numberof substituents in the saturated cyclic amide group is 1 to 3,preferably 1 or 2.

In case where the substituents in the saturated cyclic amide grouprepresented by A is the optionally substituted aliphatic hydrocarbongroup, examples of the aliphatic hydrocarbon groups are alkyl,cycloalkyl, alkenyl and alkynyl.

Examples of such alkyl groups are straight chain or branched alkylgroups having 1 to 12 carbon atoms such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, heptyl, octyl,nonyl, decyl and dodecyl, among which lower alkyl groups having 1 to 4carbon atoms (e.g., methyl, ethyl, n-propyl isopropyl, n-butyl,isobutyl, sec-butyl or tert-butyl) are preferred.

Examples of the cycloalkyl groups are cycloalkyl groups having 3 to 8carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, among which cycloalkyl groups having 3 to 6carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl)are preferred.

Examples of the alkenyl groups are alkenyl groups having 2 to 4 carbonatoms such as vinyl, propenyl and butenyl, among which alkenyl groupshaving 2 to 3 carbon atoms (e.g., vinyl or propenyl) are preferred.

Examples of the alkynyl groups are alkynyl groups having 2 to 4 carbonatoms such as ethynyl, propynyl and butynyl, among which alkynyl groupshaving 2 to 3 carbon atoms (e.g., ethynyl or propynyl) are preferred.

In case where the substituents in the saturated cyclic amide grouprepresented by A is the optionally substituted aromatic hydrocarbongroup, examples of the aromatic hydrocarbon groups are aryl groupshaving 6 to 14 carbon atoms. Examples of the aryl groups are phenyl,naphthyl, biphenylyl, anthryl and indenyl, among which aryl groupshaving 6 to 10 carbon atoms (e.g., phenyl or naphthyl) are preferred.

In case where the substituents in the saturated cyclic amide grouprepresented by A is the optionally substituted aromatic heterocyclicgroup, examples of the aromatic heterocyclic groups are aromaticheterocyclic groups having at least one hetero atom selected from anitrogen atom, a sulfur atom and an oxygen atom. The aromaticheterocyclic groups may be condensed with a benzene ring, five-memberedheterocycle or six-membered heterocycle. Examples of the aromaticheterocyclic groups are aromatic heterocyclic groups such as imidazolyl,triazolyl, tetrazolyl, pyrazolyl, pyridyl, thiazolyl, thiadiazolyl,thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl andisoxazolyl, and condensed aromatic heterocyclic group such asbenzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl,imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyland indolyl, among which five- or six-membered aromatic heterocyclicgroups having i to 3 hetero atoms optically selected from a nitrogenatom, a sulfur atom and an oxygen atom (e.g., imidazolyl, triazolyl,thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl or pyrimidinyl) arepreferred.

Examples of the substituents in the optionally substituted aliphatic oraromatic hydrocarbon group or optionally substituted aromaticheterocyclic group are a hydroxy group, optionally esterified carboxygroup (e.g., alkoxycarbonyl groups having 1 to 6 carbon atoms such ascarboxy, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl), nitrogroup, amino group, acylamino group (e.g., alkanoyl amino groups having1 to 10 carbon atoms such as acetylamino, propionylamino andbutyrylamino), alkylamino group which is mono- or di-substituted withalkyl group having 1 to 10 carbon atoms (e.g., methylamino,dimethylamino, diethylamino or dibutylamino), optionally substitutedfive- or six-membered heterocyclic group (e.g., pyrrolidinyl,morpholino, piperidino, pirazolydinyl, perhydroazepinyl, piperazinyl,4-benzylpiperazinyl, 4-acetylpiperazinyl,4-(4-trifluoromethoxyphenyl)-1-piperazinyl,4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-piperazinyl,4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl,4-[4-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl,4-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-1-piperazinyl or4-(4-trifluoromethylphenyl)-1-piperazinyl), alkoxy group having 1 to 6carbon atoms (e.g., methoxy, ethoxy or butoxy), halogen atom (e.g.,fluorine, chlorine or bromine), halogeno C₁₋₆ alkyl group (e.g.,trifluoromethyl, dichloromethyl or trifluoroethyl), halogeno C₁₋₆ alkoxygroup (e.g., trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy,2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy or2-fluoroethoxy), oxo group, thioxo group, mercapto group, alkylthiogroup having 1 to 6 carbon atoms (e.g., methylthio, ethylthio orbutylthio), alkylsulfonyl group having 1 to 6 carbon atoms (e.g.,methanesulfonyl, ethanesulfonyl or butanesulfonyl) and alkanoyl grouphaving 1 to 10 carbon atoms (e.g., acetyl, formyl, propionyl orbutyryl).

Among the substituents in the saturated cyclic amide group representedby A, optionally substituted aliphatic hydrocarbon group, optionallysubstituted aromatic hydrocarbon group and optionally substitutedaromatic heterocyclic group are preferably attached to a nitrogen atomwhich constitutes the broken line part in the ring of theabove-mentioned saturated cyclic amide group.

Preferred examples of A are an unsubstituted saturated cyclic amidegroup, a saturated cyclic amide group substituted with an oxo group, asaturated cyclic amide group substituted with a halogenophenyl group, asaturated cyclic amide group substituted with halogenophenyl and oxogroups, a saturated cyclic amide group substituted with halogenated(C₁₋₆) alkylphenyl, a saturated cyclic amide group substituted withhalogenated (C₁₋₆) alkylphenyl and oxo groups, a saturated cyclic amidegroup substituted with a halogenated (C₁₋₆) alkoxyphenyl, and asaturated cyclic amide group substituted with halogenated (C₁₋₆)alkoxyphenyl and oxo groups.

Examples of the unsubstituted saturated cyclic amide groups referred tohereinabove are 2-oxo-1-imidazolidinyl, 5-oxo-1-imidazolidinyl,2-oxo-1-pyrrolidinyl, 3-oxo-2-pyrazolidinyl, 2-oxo-1-piperazinyl,2-oxo-1-piperidinyl, 3-oxomorpholino and 2-oxo-1-perhydropyrimidinyl.

Examples of the saturated cyclic amide groups substituted with an oxogroup are 2,4-dioxo-1-imidazolidinyl, 2,5-dioxo-1-imidazolidinyl,2,4-dioxo-1-pyrrolidinyl, 3,5-dioxo-2-pyrazolidinyl,2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl and2,3-dioxo-1-piperidinyl.

Preferably, the above-mentioned unsubstituted saturated cyclic amidegroup and saturated cyclic amide group substituted with an oxo groupfurther contain a nitrogen atom in the ring in addition to a nitrogenatom bonding to a carbon bearing R¹ and R². The additional nitrogen atompreferably bonds to a substituent such as a halogenophenyl group, ahalogeno C₁₋₆ alkylphenyl group and a halogeno C₁₋₆ alkoxyphenyl groupas described below.

Examples of the saturated cyclic amide groups substituted with ahalogenophenyl group are 3-halogenophenyl-2-oxo-1-imidazolidinyl,3-halogenophenyl-2-oxo-1-pyrrolidinyl,4-halogenophenyl-2-oxo-1-piperazinyl and4-halogenophenyl-2-oxo-1-piperidinyl, among which3-halogenophenyl-2-oxo-1-imidazolidinyl is preferable.

Examples of the saturated cyclic amide groups substituted withhalogenophenyl and oxo groups are3-halogenophenyl-2,4-dioxo-1-imidazolidinyl,3-halogenophenyl-2,4-dioxo-1-pyrrolidinyl,4-halogenophenyl-2,5-dioxo-1-piperazinyl,4-halogenophenyl-2,3-dioxo-1-piperazinyl and4-halogenophenyl-2,3-dioxo-1-piperidinyl, among which3-halogenophenyl-2,4-dioxo-1-imidazolidinyl,4-halogenophenyl-2,5-dioxo-1-piperazinyl and4-halogenophenyl-2,3-dioxo-1-piperazinyl are preferable.

Examples of the saturated cyclic amide groups substituted with ahalogenated (C₁₋₆) alkylphenyl are 3-halogenated (C₁₋₆)alkylphenyl-2-oxo-1-imidazolidinyl, 3-halogenated (C₁₋₆)alkylphenyl-2-oxo-1-pyrrolidinyl, 4-halogenated (C₁₋₆)alkylphenyl-2-oxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkylphenyl-2-oxo-1-piperidinyl, among which 3-halogenated (C₁₋₆)alkylphenyl-2-oxo-1-imidazolidinyl is preferable.

Examples of the saturated cyclic amide groups substituted withhalogenated (C₁₋₆) alkylphenyl and oxo groups are 3-halogenated (C₁₋₆)alkylphenyl-2,4-dioxo-1-imidazolidinyl, 3-halogenated (C₁₋₆)alkylphenyl-2,4-dioxo-1-pyrrolidinyl, 4-halogenated (C₁₋₆)alkylphenyl-2,5-dioxo-1-piperazinyl, 4-halogenated (C₁₋₆)alkylphenyl-2,3-dioxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkylphenyl-2,3-dioxo-1-piperidinyl, among which 3-halogenated (C₁₋₆)alkylphenyl-2,4-dioxo-1-imidazolidinyl, 4-halogenated (C₁₋₆)alkylphenyl-2,5-dioxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkylphenyl-2,3-dioxo-1-piperazinyl are preferable.

Examples of the saturated cyclic amide groups substituted withhalogenated (C₁₋₆) alkoxyphenyl are 3-halogenated (C₁₋₆)alkoxyphenyl-2-oxo-1-imidazolidinyl, 3-halogenated (C₁₋₆)alkoxyphenyl-2-oxo-1-pyrrolidinyl, 4-halogenated (C₁₋₆)alkoxyphenyl-2-oxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkoxyphenyl-2-oxo-1-piperidinyl, among which 3-halogenated (C₁₋₆)alkoxyphenyl-2-oxo-1-imidazolidinyl is preferable.

Examples of the saturated cyclic amide groups substituted withhalogenated (C₁₋₆) alkoxyphenyl and oxo groups are 3-halogenated (C₁₋₆)alkoxyphenyl-2,4-dioxo-1-imidazolidinyl, 3-halogenated (C₁₋₆)alkoxyphenyl-2,4-dioxo-1-pyrrolidinyl, 4-halogenated (C₁₋₆)alkoxyphenyl-2,5-dioxo-1-piperazinyl, 4-halogenated (C₁₋₆)alkoxyphenyl-2,3-dioxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkoxyphenyl-2,3-dioxo-1-piperizinyl , among which 3-halogenated (C₁₋₆)alkoxyphenyl-2,4-dioxo-1-imidazolidinyl, 4-halogenated (C₁₋₆)alkoxyphenyl-2,5-dioxo-1-piperazinyl and 4-halogenated (C₁₋₆)alkoxyphenyl-2,3-dioxo-1-piperazinyl are preferable.

More preferred examples of A are a saturated cyclic amide groupsubstituted with a halogenophenyl group, a saturated cyclic amide groupsubstituted with halogenophenyl and oxo groups, a saturated cyclic amidegroup substituted with a halogenated (C₁₋₆) alkylphenyl, a saturatedcyclic amide group substituted with halogenated (C₁₋₆) alkylphenyl andoxo groups, a saturated cyclic amide group substituted with ahalogenated (C₁₋₆) alkoxyphenyl and a saturated cyclic amide groupsubstituted with halogenated (C₁₋₆) alkoxyphenyl and oxo groups.

Most preferred examples of A are 3-halogenophenyl-2-oxo-1-imidazolidinyl(e.g., 3-(2,4-difluorophenyl)-2-oxo-1-imidazolidinyl or3-(4-fluorophenyl)-2-oxo-1-imidazolidinyl), 3-halogenated lower (C₁₋₄)alkylphenyl-2-oxo-1-imidazolidinyl (e.g.,3-(4-trifluoromethylphenyl)-2-oxo-1-imidazolidinyl), 3-halogenated lower(C₁₋₄) alkoxyphenyl-2-oxo-1-imidazolidinyl (e.g.,3-(4-trifluoromethoxyphenyl)-2-oxo-1-imidazolidinyl,3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-oxo-1-imidazolidinyl,3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-oxo-1-imidazolidinyl,3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2-oxo-1-imidazolidinyl or3-[4-(-2,2,2-trifluoroethoxy)phenyl]-2-oxo-1-imidazolidinyl).

Particularly preferred examples of optionally-substituted saturatedcylcic amide groups bonded through a nitrogen atom are a 3-substitutedphenyl-2-oxo-1-imidazolidinyl of the formula: ##STR9## wherein R⁴ is asubstituted phenyl group, or a 4-substitutedphenyl-2,5-dioxo-1-piperazinyl of the formula: ##STR10## wherein R⁵ hasthe same meaning as R⁴.

Examples of the substituted phenyl groups represented by R⁴ and R⁵ are ahalogenophenyl group, a halogenated (C₁₋₆) alkylphenyl group, ahalogenated (C₁₋₆) alkoxyphenyl group, which are mentioned as thesubstituents in the saturated cyclic amide group.

The compound (I) can be also used as a salt thereof and examples of suchsalts are a pharmacologically-acceptable salts such as a salt withinorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid or phosphoric acid) and a salt with organic acid(e.g., acetic acid, tartaric acid, citric acid, fumaric acid, maleicacid, toluenesulfonic acid or methanesulfonic acid).

The compound represented by a formula (I) or a salt thereof(hereinafter, referred to as the compound of the present invention) hasone or more asymmetric carbon(s) in its molecule and, therefore, thereare two or more stereoisomers. Any of such stereoisomers as well as amixture thereof is within a scope of the present invention. Among those,the optically active substances that when R¹ is a hydrogen atom and R²is a methyl group, both of the carbon atom to which theoptionally-substituted phenyl group represented by Ar is bonded andanother carbon atom to which R² is bonded are in the (R)-configurationsare particularly preferred.

The compound of the present invention can be manufactured by, forexample, reacting of a compound of the formula (II): ##STR11## whereinthe symbols have the same meanings as defined above, with a compound ofthe formula (III): ##STR12## wherein the symbols have the same meaningsas defined above, or a salt thereof, if necessary followed by treatingwith an acylating agent.

The reaction can be usually conducted out in a solvent which does notimpede the reaction. Examples of the solvents which does not impede thereaction are water; ketones such as acetone; sulfoxides such as dimethylsulfoxide; ethers such as diethyl ether, tetrahydrofuran and dioxane;nitriles such as acetonitrile; aromatic hydrocarbons such as benzene,toluene and xylene; halogenated hydrocarbons such as dichloromethane,chloroform and 1,2-dichloroethane; esters such as ethyl acetate; amidessuch as dimethylformamide, acetamide, dimethylacetamide and1-methyl-2-pyrrolidinone; ureylenes such as1,3-dimethyl-2-imidazolidinone; and the like. They may be used eithersingly or as a mixture thereof in a suitable mixing ratio.

Further, it is preferred that the above reaction is conducted out in thepresence of a base such as alkali metal hydroxides (e.g., lithiumhydroxide, potassium hydroxide or sodium hydroxide), alkali metalhydrides (e.g., potassium hydride or sodium hydride), alkali metalcarbonates (e.g., lithium carbonate, sodium bicarbonate, cesiumcarbonate, potassium carbonate or sodium carbonate), organic acid salts(e.g., sodium acetate), alkali metal alcoholates (e.g., sodium methylateor potassium tert-butylate), tetrabutylammonium fluoride andbis(tri-n-butylstannyl)oxide.

Alternatively, the desired compound can be manufactured by the reactionin the above-mentioned solvent using a salt of the compound (III) withmetal (e.g., alkali metal such as sodium and potassium) instead of thecompound (III).

The amount of the base used is usually about 0.001 to 100 equivalents,preferably about 0.01 to 50 equivalents, to the compound (II).

The amount ot the compound (III) or salt thereof is about 1 to 100equivalents, preferably about 1 to 50 equivalents, to the compound (II).

The reaction temperature is not particularly limited but, usually it isabout 0° to 150° C., preferably about 10° to 120° C.

The reaction time is usually about several minutes to several ten hours(for example, from five minutes to fifty hours).

The compound of the present invention can be manufactured by, forexample, reacting a compound of the formula (IV): ##STR13## wherein thesymbols have the same meanings as defined above, or the salt thereof

with a compound of the formula (V):

    H--A                                                       (V)

wherein the symbols have the same meanings as defined above, or the saltthereof to give a compound of formula (I) in which R³ is a hydrogenatom.

The above reaction can be usually conducted in a solvent which does notimpede the reaction. Examples of such solvents are water; ketones suchas acetone; sulfoxides such as dimethyl sulfoxide; ethers such asdiethyl ether, tetrahydrofuran and dioxane; nitriles such asacetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; esters such as ethyl acetate; amides such asdimethylformamide, acetamide, dimethylacetamide and1-methyl-2-pyrrolidinone; ureylenes such as1,3-dimethyl-2-imidazolidinone; and the like. They may be used eithersingly or as a mixture thereof in a suitable mixing ratio.

Further, it is preferred that the above reaction is conducted in thepresence of a base such as alkali metal hydroxides (e.g., lithiumhydroxide, potassium hydroxide or sodium hydroxide), alkali metalhydrides (e.g., potassium hydride or sodium hydride), alkali metalcarbonates (e.g., lithium carbonate, sodium bicarbonate, cesiumcarbonate, potassium carbonate or sodium carbonate), organic acid salts(e.g., sodium acetate), alkali metal alcoholates (e.g., sodium methylateor potassium tert-butylate), tetrabutylammonium fluoride,bis(tri-n-buthylstannyl)oxide, and the like, among whichtetrabutylammonium fluoride is preferred.

Alternatively, the desired compound can be manufactured by the reactionin the above-mentioned solvent using a salt of the compound (V) withmetal (e.g., alkali metal such as sodium and potassium) instead of thecompound (V).

The amount of the base is usually about 0.001 to 100 equivalents,preferably about 0.01 to 50 equivalents, to the compound of the formula(V).

The amount of the compound (V) or salt thereof is about 0.1 to 100equivalents, preferably about 0.1 to 50 equivalents, to the compound(IV).

The reaction temperature is not particularly limited but, usually it isabout 0° to 150° C. preferably about 10° to 120° C.

The reaction time is usually about several minutes to several ten hours(e.g., five minutes to fifty hours).

The compound of the formula (I) wherein A is an optionally-substituted2-oxo-1-imidazolidinyl or a salt thereof can be manufactured by, forexample, subjecting a compound of the formula (VI): ##STR14## wherein A'is an optionally-substituted 2-oxo-2,3-dihydro-1H-imidazol-1-yl groupand the other symbols have the same meanings as defined above, or a saltthereof to a catalytic reduction reaction.

The above-mentioned reaction is usually conducted in the presence ofwater or an organic solvent which does not impede the reaction such asketones (e.g., acetone or methyl ethyl ketone), alcohols (e.g.,methanol, ethanol, propanol, isopropyl alcohol or butanol), esters(e.g., ethyl acetate), hydrocarbons (e.g., benzene, toluene, hexane orxylene), organic carboxylic acids (e.g., acetic acid or propionic acid),and the like, which may be used either singly or as a mixture thereof.This reaction is usually conducted in the presence of a catalyst. Withrespect to the catalyst, a suitable metal catalyst such aspalladium-carbon is used. This reduction reaction is conducted underfrom an atmospheric pressure to a pressure of up to about 150 kg/cm² atthe temperature of from room temperature to about 100° C.

Examples of the salts of the above-mentioned starting compounds (III),(IV) and (VI) are the same as those of the compound (I).

When a compound of the formula (I) wherein R³ is a hydrogen atom isobtained by the above-mentioned reactions, the compound or the saltthereof can be acylated to give another compound of the formula (I)wherein R³ is an acyl group, by treating it with an appropriateacylating agent of R³ X (R³ is an aliphatic or aromatic hydrocarbonresidue such as acetyl, propionyl, butyryl, ethoxycarbonyl, benzoyl andsubstituted benzoyl; and X is a leaving group such as a halogen atom,e.g., chlorine or bromine or activated ester group).

The above-mentioned reaction is usually conducted in the absence orpresence of a solvent which does not impede the reaction. Examples ofsuch solvents are ketones such as acetone; sulfoxides such as dimethylsulfoxide; ethers such as diethyl ether, tetrahydrofuran and dioxane;nitriles such as acetonitrile; aromatic hydrocarbons such as benzene,toluene and xylene; halogenated hydrocarbons such as dichloromethane,chloroform and 1,2-dichloroethane; esters such as ethyl acetate; amidessuch as dimethylformamide, acetamide and demethylacetamide; ureylenessuch as 1,3-dimethyl-2-imidazolidinone; and the like. For accelerationof the reaction rate, a base (e.g., dimethylaminopyridine, piridine,picolin or triethylamine) can be added to the reaction system.

The compound of the present invention can be isolated and purified fromthe reaction mixture by a known procedure per se such as extraction,concentration, neutralization, filtration, recrystallization, columnchromatography and thin layer chromatography.

The compound of the present invention can have at least twostereoisomers. Each of such isomers and each of mixtures thereof isincluded in the concept of the present invention and, if desired, suchan isomer can be manufactured separately. For example, a single isomerof the compound of the present invention can be obtained by theabove-mentioned reaction starting from each single isomer of thestarting compounds (II), (IV) and (VI). When the product is a mixture oftwo or more isomers, they may be separated into each isomer by aconventional separating method such as a method of producing salt withan optically-active acid (e.g., camphorsulfonic acid or tartaric acid)or by means of various types of chromatographies, fractionalrecrystallization and so on.

The salt of the compound (I) can be manufactured by a known method pe sesuch as by adding the above-mentioned inorganic or organic acid to thecompound (I).

The starting compound (II) in the present invention wherein R¹ is ahydrogen atom, R² is a methyl group, the carbon to which Ar is bonded isin an (S)-configuration and the carbon to which R² is bonded is in an(R)-configuration (i.e., a compound (VII)) can be manufactured by amethod as given in the following scheme. ##STR15## wherein Me is amethyl group, Et is a ethyl group, Pr is a propyl group, Ph is a phenylgroup, DMF is dimethyl formamide and the other symbols have the samemeanings as defined above.

The starting compound (VIII) in the scheme can be manufactured by amethod as given in the following scheme. ##STR16## wherein THP is atetrahydropyranyl group, DMSO is dimethylsulfoxide and the other symbolshave the same meanings as defined above.

The starting compound (VI) in the present invention wherein R¹ is ahydrogen atom , R² is a methyl group, R³ is a hydrogen atom and both acarbon to which Ar is bonded and a carbon to which R² is bonded are in(R)-configurations (i.e., a compound (XVII)) can be manufactured by, forexample, a method as given in the following scheme. ##STR17## whereinthe symbols have the same meanings as defined above.

The starting compound (XX) in the scheme can be synthesized by a methoddisclosed in EP0548553A or EP0421210A.

The starting compound (XVIII) in the present invention wherein A' is a3-substituted-2-oxo-2,3-dihydro-1H-imidazol-1-yl group (i.e., a compound(XXI)) can be manufactured by, for example, a method as given in thefollowing scheme. ##STR18## wherein R^(4') is a substituent in theabove-mentioned A and the other symbols have the same meanings asdefined above.

The compound (V) wherein A is a 3-substituted-2-oxo-1-imidazolidinyl(i.e., a compound (XXIV)) can be manufactured by, for example, a methodas given in the following scheme. ##STR19## wherein the symbols have thesame meanings as defined above.

The compound (V) wherein A is a 4-substituted-2,5-dioxo-1-piperazinyl(i.e., a compound (XXV)) can be manufactured by, for example, a methodas given in the following scheme. ##STR20## wherein R^(5') is asubstituent in the above-mentioned A and the other symbols have the samemeanings as defined above.

The compound (V) wherein A is a 4-substituted-2,3-dioxo-1-piperazinyl(i.e., a compound (XXVIII)) can be manufactured by a method as given inthe following scheme. ##STR21## wherein the symbols have the samemeanings as defined above.

Further, the intermediate compound (IX) in the present invention can bemanufactured by, for example, a method as given in the following scheme.##STR22## wherein the symbols have the same meanings as defined above.

The above-mentioned starting compounds can be isolated and purified fromthe reaction mixture by a known procedure per se such as extraction,concentration, neutralization, filtration, recrystallization, columnchromatography, thin layer chromatograhy, etc.

The compound of the present invention has low toxicity and exhibits highantifungal activities with broad antifungal spectrum against, forexample, microorganisms of genus Candida (e.g., Candida albicans,Candida utilis, Candida grabrata etc.), those of genus Aspergillus(e.g., Aspergillus niger, Aspergillus fumigatus, etc.), those of genusCryptococcus (e.g., Cryptococcus neoformans, etc.), those of genusTricophyton (e.g., Trichophyton rubrum, Trichophyton mentagrophytes,etc.), those of genus Microsporum (e.g., Microsporum gypseum, etc.) andthe like and, therefore, it can be used for prevention and therapy ofthe fungal infections (e.g., candidiasis, histoplasmosis, aspergillosis,cryptococcosis, trichophytosis, microsporumosis, etc.) of mammals (e.g.,human being, domestic animals, fowls, etc.). Further, the compound ofthe present invention can be also used as an antifungal preparation foragricultural use.

The starting compound (VI) for manufacturing the compound (I) of thepresent invention wherein R³ is a hydrogen atom has also antifungalactivities against the above-mentioned microorganisms.

When the compound of the present invention is administered to humanbeing, it can be safely administered either orally or parenterally inthe form of pharmaceutical compositions such as oral administrationpreparations (e.g., powders, granules, tablets, capsules, etc.),parenteral administration preparations [e.g., injections, externalpreparations (e.g., nasal or dermatological ones), suppositories (e.g.,rectal or vaginal ones)], and the like in per se or by mixing withsuitable pharmacologically-acceptable carriers, excipients, diluents,etc.

Those preparations can be manufactured by the methods which are knownper se and commonly used in the manufacture of pharmaceuticalpreparations.

For example, the compound of the present invention can be made intoinjections such as aqueous injections together with dispersing agents(e.g., Tween 80 [Atlas Powder, U.S.A.], HCO60 [Nikko Chemicals, Japan],carboxymethylcellulose, sodium alginate, etc.), preservatives (e.g.,methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.),isotonic agents (e.g., sodium chloride, glycerol, sorbitol, glucose,etc.) and the like, or as oily injections by dissolving, suspending oremulsifying in a plant oil (e.g., olive oil, sesame oil, peanut oil,cotton seed oil, corn oil, etc.), propylene glyocol and the like.

In the manufacture of preparations for oral administration, the compoundof the present invention is molded with presure together, for example,with excipients (e.g., lactose, sugar, starch, etc.), disintegratingagents (e.g., starch, calcium carbonate, etc.), binders (e.g., starch,gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, etc.), lubricants (e.g., talc, magnesiumstearate, polyethylene glycol 6000, etc.) and the like followed, ifnecessary, by coating in accordance with a known method per se with anobject of taste-masking or of providing the preparation with enteric orsustained release property. Examples of the coating agents are, forexample, hydroxypropylmethylcellulose, ethylcellulose,hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol,Tween 80, Pluronic F68, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, Eudragit (Rohm, West Germany; a copolymer of methacrylic acidwith acrylic acid) and pigments such as titanium oxide and red ironoxide.

In the case of preparation for external use, the compound of the presentinvention can be also made into a solid, semisolid or liquidpreparation. For example, in the case of a solid preparation, thecompound of the present invention is used as it is or mixed withexcipients (e.g., glucose, mannitol, starch, microcrystalline cellulose,etc.), thickeners (e.g., natural gums, cellulose derivatives, acrylicacid polymers, etc.) and the like to give powdered compositions. In thecase of a semisolid preparation, an aqueous or oily gel preparation oran ointment is preferred. In the case of a liquid preparation, theprocedures are nearly the same as those in the case of injections togive oily or aqueous suspensions. The above-mentioned solid, semisolidor liquid preparations can be added with pH adjusting agents (e.g.,carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodiumhydroxide, etc.), antiseptics (e.g., p-hydroxybenzoates, chlorobutanol,benzalkonium chloride, etc.) or the like. More specifically, it can beused for sterilization or disinfection of skin or mucous membrane as anointment containing, for example, about 0.1 to 100 mg of the compound ofthe present invention per gram using vaselin or lanoline as a basematerial.

In the case of suppositories, the compound of the present invention canbe made into oily or aqueous suppositories in solid, semisolid orliquid. Examples of the oily base materials used therefor are higherfatty acid glycerides (e.g., cacao butter, Witepsols [Dynamite-Nobel],etc.), medium fatty acids (e.g., Migriols [Dynamite-Nobel], etc.), plantoil (e.g., sesame oil, soybean oil, cotton seed oil, etc.) and the like.Examples of the aqueous base material are polyethylene glycols,propylene glycols, etc., while those of the aqueous gel base materialsare natural gums, cellulose derivatives, vinyl polymers, acrylic acidpolymers, etc.

Dose of the compound of the present invention may vary depending uponthe state of infection, the route of administration, etc. and, in thecase of giving it to an adult patient (body weight: 50 kg) for thetherapy of candidiasis for example, the dose is about 0.01 to 100mg/kg/day, preferably about 0.1 to 50 mg/kg/day and, more preferably,about 0.1 to 20 mg/kg/day by oral route.

When the compound of the present invention is used as an agriculturalantifungal agent, it is dissolved or dispersed in a suitable liquidcarrier (e.g., solvents) or mixed or adsorbed with a suitable solidcarrier (e.g., diluents or fillers) followed, if necessary, by addingemulsifier, suspending agent, spreader, penetrating agents, moisturizingagent, thickener, stabilizer, etc. to give the preparation such asemulsion, hydrating agent, powder, granules and the like. Suchpreparations can be prepared by a known method per se. The amount of thecompound of the present invention is, for example in the case of a riceblast diseases, about 25 to 150 g, preferably about 40 to 80 g, per acreof irrigated rice field.

Examples of the liquid carriers are water, alcohols (e.g., methylalcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethyleneglycol, etc.), ethers (e.g., dioxane, tetrahydrofuran, etc.), aliphatichydrocarbons (e.g., kerosene, lamp oil, fuel oil, etc.), aromatichydrocarbons (e.g., benzene, toluene, etc.), halogenated hydrocarbons(e.g., methylene chloride, chloroform, etc.), acid amides (e.g.,dimethylformamide, dimethylacetamide, etc.), esters (e.g., ethylacetate, butyl acetate, etc.), nitriles (e.g., acetonitrile,propionitrile, etc.) and the like. They may be used either singly or asa mixture thereof in a suitable mixing ratio.

Examples of the solid carriers are plant powder (e.g., soybean powder,tabacco powder, wheat flour, etc.), mineral powder (e.g., kaolin,bentonite, etc.), alumina, sulfur powder, activated charcoal and thelike. They may be used either singly or as a mixture thereof in asuitable mixing ratio.

EXAMPLES

The present invention will be further illustrated by way of thefollowing reference examples, working examples and preparation examples.However, it is not intended to limit the scope of the present inventionthereto.

¹ H-NMR spectra were measured by a spectrometer of Varian Gemini 200type (200 MHz) using tetramethylsilane as an internal standard. All δvalue are given by ppm. In the mixing solvents, the figures given in ()are the mixing ratio of each of the solvents by volume. Unless otherwisespecified, the symbol % means that by weight. In the silica gelchromatography, the ratio of the solvents is a ratio of the mixedsolvents by volume.

The symbols used in the examples have the following meanings.

s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; tt:triple triplet; m: multiplet; quintet:quintet; septet:septet; br: broad;J: coupling constant.

Reference Example 1

2-(2,4-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane(82 g) (sythesized by a method disclosed in the Japanese Laid-OpenPublication Hei-04/74168) and 6.3 g of pyridinium p-toluenesulfonte weredissolved in 600 ml of ethanol and the solution was stirred at 55° C.for one hour. The reaction solution was concentrated under reducedpressure. The residue was dissolved in one liter of ethyl acetate andthe resulting solution was washed with water (2×200 ml). The aqueouslayer was extracted with ethyl acetate (2×100 ml). The organic layerswere combined, washed with a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate and distilled off under reducedpressure. The residue was purified by silica gel chromatography(eluent:hexane/ethyl acetate=10/1 to 8/1 to 3/1) to give 31.5 g of(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellow oil.

¹ H-NMR (CDCl₃) δ: 1.14-1.23 (3H,m), 1.77, 2.22 (1H), 2.80, 2.92 (1H),3.27-3.32 (1H), 4.00-4.20 (1H,m), 6.75-6.94 (2H,m), 7.36-7.48 (1H,m).

Reference Example 2

(1R)-1-[2-(2,4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 40 g of3,5-dinitrobenzoyl chloride were dissolved in 500 ml of methylenechloride and, with ice cooling, 24.1 ml of triethylamine was addeddropwise thereinto. The reaction solution was stirred at roomtemperature for 3.5 hours, washed with 150 ml of water and then with 150ml of 5% aqueous solution of sodium bicarbonate, dried over magnesiumsulfate and concentrated under reduced pressure. The crystals separatedout were collected by filtration and washed with methylene chloride. Themother liquor and the washing were combined and distilled off underreduced pressure, then 25 ml of ethyl acetate and 300 ml of methanolwere added to the residue and the mixture was cooled with ice. Thecrystals separated out were collected by a filtration and recrystallizedfrom a mixture of 25 ml of ethyl acetate and 250 ml of methanol to give28.7 g of[(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoateas colorless needles.

mp 104°-107° C. (recrystallized from ethyl acetatehexane).

¹ H-NMR (CDCl₃) δ: 1.46 (3H,dd,J=6.6 Hz,J=1.2 Hz), 3.01 (1H,d,J=4.6 Hz),3.23 (1H,d,J=4.6 Hz), 5.33 (1H,q,J=6.6 Hz), 6.85-7.07 (2H,m), 7.54(1H,m), 9.13 (2H,d,J=2.2 Hz), 9.25 (1H,t,J=2.2 Hz).

Reference Example 3

[(1R )-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoate (50 g) wasdissolved in two liters of methanol and, at room temperature, 255 ml of1N sodium hydroxide was added dropwise thereinto. The reaction solutionwas stirred at room temperature for one hour and neutralized with 127 mlof 1N hydrochloric acid. Methanol was distilled off under reducedpressure, then one liter of ethyl acetate and 200 ml of water were addedto the residue, and the mixture was extracted with ethyl acetate. Theorganic extract was washed with 200 ml of a saturated aqueous solutionof sodium chloride, dried over magnesium sulfate and distilled off underreduced pressure. The residue was purified by silica gel chromatography(eluent: ethyl acetate/hexane=1/3) to give 25 g of(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellowoil.

¹ H-NMR (CDCl₃) δ: 1.17 (3H,dd,J=6.6 Hz,1.2 Hz), 2.05 (1H,br), 2.80(1H,d,J=5.2 Hz), 3.30 (1H,d,J=5.2 Hz), 4.01-4.17 (1H,m), 6.75-6.93(2H,m), 7.36-7.48 (1H,m).

Reference Example 4

To a solution of 16.1 g of(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol in 320 ml oftetrahydrofuran were added, with ice cooling, 63.3 g oftriphenylphosphine, 29.5 g of benzoic acid and 42.0 g of diethylazodicarboxylate and the mixture was stirred at room temperature for sixhours under an atmosphere of argon. To the reaction solution were added800 ml of ethyl acetate and 500 ml of water to fractionate and theaqueous layer was extracted with 200 ml of ethyl acetate. The organiclayers were combined, washed successively with water and a saturatedaqueous solution of sodium chloride, then dried over magnesium sulfateand concentrated, The residue was purified by silica gel chromatography(eluent: hexane/ethyl acetate=15/1 to 7/1) to give 19.2 g of[(1S)-1-[(2R)-2-(2,4-difluororphenyl)-2-oxiranyl]ethyl]benzoate as acolorless oil.

¹ H-NMR (CDCl₃) δ: 1.37 (3H,d,J=6.6 Hz), 2.90 (1H,d,J=5.2 Hz), 3.28(1H,d,J=5.2 Hz), 5.36 (1H,q,J=6.6 Hz), 6.74-6.94 (2H,m), 7.38-7.60(4H,m), 7.94-8.01 (2H,m).

IR ν^(neat) _(max) cm⁻¹ : 1725, 1615, 1600, 1505, 1450, 1425.

[(1S)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl]benzoate (15.9 g)was dissolved in 800 ml of methanol, and 12.9 ml of 28% methanolicsolution of sodium methylate was added thereto with ice cooling. Thereaction solution was stirred for six hours at room temperature. To thereaction solution was added 63.2 ml of 1N hydrochloric acid and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel chromatography (eluent: hexane/ethyl acetate=6/1to 2/1) to give 9.7 g of(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a colorlessoil.

¹ H-NMR (CDCl₃) δ: 1.20 (3H,dd,J=6.4 Hz,2.2 Hz), 2.24 (1H,d,J=1 Hz),2.92 (1H,d,J=5 Hz), 3.28 (1H,d,J=5 Hz), 4.12 (1H,q,J=6.4 Hz), 6.77-6.95(2H, m), 7.34 (1H, m).

IR ν^(neat) _(max) cm⁻¹ : 3420, 2980, 1615, 1600, 1500, 1425.

Reference Example 5

2,4-Difluroaniline (25 g) and 25.2 g of pyridine were dissolved in 200ml of dichloromethane and, with ice cooling, 33.3 g of phenylchloroformate was added dropwise thereinto. The reaction solution wasstirred with ice cooling for 30 minutes, washed with water and dried.The solvent was distilled off to give a mixture of phenyl2,4-difluorophenylcarbamate and pyridine. To the mixture was added 30.7g of 2-(diethoxy)ethylamine, and the resulting mixture was stirred atroom temperature. The crystals separated out were collected byfiltration and washed with petroleum ether to give 37.8 g ofN-(2,2-diethoxyethyl)-N'-(2,4-difluorophenyl)urea as colorless crystals.

This urea compound (37.5 g) was dissolved in a mixture of 560 ml ofmethanol and 280 ml of water, 300 ml of 0.48M hydrochloric acid wasadded thereto and the mixture was stirred at room temperature for threedays. The reaction solution was concentrated under reduced pressure andthe crystals separated out were washed with a mixture of water andmethanol (5:1) to give 22.8 g of1-(2,4-difluorophenyl)-2-(1H,3H)-imidazolone as a colorless powder.

mp 192°-194° C.

Elemental analysis for C₉ H₆ F₂ N₂ O Calcd (%): C 55.11, H 3.08, N 14.28Found (%): C 55.14, H 3.29, N 14.18

Reference Examples 6-13

In the same manner as in Reference Example 5, the imidazolonederivatives shown in Table 1 were obtained.

                  TABLE 1                                                         ______________________________________                                         ##STR23##                                                                    Ref. Ex. No.                                                                            R.sup.4             mp (°C.)                                 ______________________________________                                         6                                                                                       ##STR24##          145-146                                          7                                                                                       ##STR25##          170-171                                          8                                                                                       ##STR26##          166-167                                          9                                                                                       ##STR27##          157-159                                         10                                                                                       ##STR28##          161-163                                         11                                                                                       ##STR29##          147-150                                         12                                                                                       ##STR30##          145-151                                         13                                                                                       ##STR31##          176-178                                         ______________________________________                                    

Reference Example 14

Phenyl 2,4-difluorophenylcarbamate (5.0 g) and 4.2 g of glycine ethylester hydrochloride were dissolved in 30 ml of pyridine and the solutionwas heated at 80° C. for 14 hours. The reaction solution wasconcentrated under reduced pressure and to the residue were added 80 mlof ethyl acetate and 20 ml of water. The ethyl acetate layer was washedwith 10 ml of an aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Hexane (50 ml) was added to the residue and the solid separated out wascollected by filtration to give 4.58 g ofN-(2,4-difluorophenyl)-N'-ethoxycarbonylmethylurea as a colorlesspowder.

¹ H-NMR (CDCl₃) δ: 1.29 (3H,t,J=7 Hz), 4.07 (2H,d,J=5.4 Hz), 4.24(2H,q,J=7 Hz), 5.57 (1H,br), 6.75-6.90 (3H,m) 7.84-7.98 (1H,m).

The product (4.1 g) was dissolved in 80 ml of methanol, 3.0 g of 28%methanolic solution of sodium methoxide was added thereto and themixture was stirred at room temperature for 2.5 hours. To the reactionsolution was added 15 ml of 1N hydrochloric acid, the mixture wasconcentrated under reduced pressure, and then 20 ml of water was addedto the residue. The mixture was extracted with 80 ml of ethyl acetate.The extract was washed successively with 20 ml of water and 20 ml of asaturated aqueous solution of sodium chloride and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was crystallized from diethyl ether to give 1.0 gof 3-(2,4-difluorophenyl)-2,4-imidzolidinedione as a colorless powder.

mp 161°-170° C.

¹ H-NMR (CDCl₃) δ: 4.20 (2H,s), 5.90 (1H,br), 6.95-7.10 (2H,m),7.25-7.40 (1H,m).

Reference Example 15

1-[(4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2(1H,3H)-2-imidazolone (2.0 g)was dissolved in 10 ml of acetic acid, 0.5 g of 10% palladium-carbon wasadded thereto and the mixture was stirred for 7.5 hours in an atmosphereof hydrogen. The catalyst was filtered off, the catalyst was washed withacetic acid. The filtrate and the washing were combined and distilledoff under reduced pressure. To the residue was added each 40 ml of waterand ethyl acetate to fractionate, and the ethyl acetate layer was dried(over MgSO₄) and distilled off under reduced pressure. The resultingcolorless crystals were washed with diisopropyl ether to give 1.86 g of1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone as colorlesscrystals.

mp 180°-181° C.

¹ H-NMR (CDCl₃) δ: 3.53-3.61 (2H,m), 3.87-3.95 (2H,m), 4.32(2H,tt,J=11.8 Hz,1.6 Hz), 4.97 (1H,brs), 6.06 (1H,tt,J=53 Hz,5.0 Hz),6.91 (2H,d,J=9.2 Hz), 7.47 (2H,d,J=9.2 Hz).

IR (KBr)ν_(max) : 3250, 1705, 1680, 1515, 1485 (cm⁻¹).

Elemental analysis for C₁₂ H₁₂ F₄ N₂ O₂ Calcd (%): C 49.32, H 4.14, N9.59 Found (%): C 49.24, H 3.96, N 9.59

Reference Examples 16-19

In the same manner as in Reference Example 15, the imidazolidinonesgiven in Table 2 were obtained.

                  TABLE 2                                                         ______________________________________                                         ##STR32##                                                                    Ref. Ex. No.                                                                             R.sup.4            mp (°C.)                                 ______________________________________                                        16                                                                                        ##STR33##         169-171                                         17                                                                                        ##STR34##         190-192                                         18                                                                                        ##STR35##         188-189                                         19                                                                                        ##STR36##         160-165                                         ______________________________________                                    

Reference Example 20

Diisopropylethylamine (0.51 ml) was added to a solution of 535 mg of(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol in 15 ml ofdichloromethane at -78° C. under an atmosphere of nitrogen and then 0.49ml of trifluoromethanesulfonic acid anhydride was added dropwisethereinto over the period of three minutes. The mixture was stirred at-78° C. for 20 minutes, then at -20° C. for 20 minutes and the reactionsolution was concentrated to about 9 ml at -10° C. The concentratedsolution was subjected to flush column chromatography using silica gel(3.2×4 cm) and eluted with dichloromethane-hexane (1:1). The fractioncontaining the product was concentrated to about 3 ml. The residue wasadded, at -10° C., to a solution of sodium salt of1-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone prepared from 606 mg of1-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone, 3 ml ofdimethylformamide and 85 mg of 60% sodium hydride in oil and the mixturewas stirred for ten minutes. The reaction solution was stirred at 0° C.for 20 minutes. Water (30 ml) was added to the reaction solution and themixture was extracted with 30 ml of ethyl acetate four times. The ethylacetate layer was washed successively with 20 ml of water twice and asaturated aqueous solution of sodium chloride once, and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure to give a colorless oily product. This product was purified bysilica gel chromatography (eluent: hexane/ethyl acetate=3/1 to 2/1 to1/1) to give 362 mg of1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazoloneand 209 mg of(2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethylphenyl)-2-imidazolyloxy]ethyl]oxirane.

1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone:colorless prisms.

mp 135°-136° C.

¹ H-NMR (CDCl₃) δ: 1.37 (3H,d,J=7.2 Hz), 2.72 (1H,d,J=4.4 Hz), 2.82(1H,d,J=4.4 Hz), 5.09 (1H,q,J=7.2 Hz), 6.50 (1H,d,J=3.2 Hz), 6.64(1H,d,J=3.2 Hz), 6.80-6.97 (2H,m), 7.35-7.50 (1H,m), 7.69 (2H,d,J=8.4Hz), 7.82 (2H,d,J=8.4 Hz).

60% Sodium hydride in oil (65 mg) was dispersed in 4 ml ofdimethylformamide, and 118 mg of 1,2,4-triazole was added thereto withice cooling. The resulting mixture was stirred at room temperature forten minutes. The solution of 362 mg of1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazoloneprepared hereinabove in 2 ml of dimethylformamide was added thereto andthe resulting mixture was heated at 50° C. for five hours. Aftercooling, to the reaction solution was added 8 ml of cold water and 40 mlof ethyl acetate to fractionate and the aqueous layer was extracted withethyl acetate twice. The ethyl acetate layers were combined, washed withwater and a saturated aqueous solution of sodium chloride successively,dried over anhydrous magnesium sulfate and distilled off under reducedpressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate/hexane=1/1 to 2/1 to ethyl acetate) to give 350 mg of1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone as a colorless powder.

¹ H-NMR (CDCl₃) δ: 1.21 (3H,d,J=7.2 Hz), 4.19 (1H,d,J=14.2 Hz), 5.00(1H,q,J=7.2 Hz), 5.11 (1H,d,J=14.2 Hz), 5.46 (1H,s), 6.71 (1H,d,J=3.2Hz), 6.83 (1H,d,J=3.2 Hz) 6.72-6.90 (2H,m), 7.40-7.56 (1H,m), 7.72(2H,d,J=8.4 Hz), 7.75 (1H,s), 7.83 (2H,d,J=8.4 Hz), 7.84 (1H,s).

IR ν^(neat) _(max) cm⁻¹ : 3404 , 3383, 3000, 1693, 1618, 1599, 1524,1500, 1429, 1327.

Elemental analysis for C₂₂ H₁₈ F₅ N₅ O₂ Calcd (%): C 55.12, H 3.78, N14.61 Found (%): C 54.81, H 3.97, N 14.39

Reference Examples 21-23

The following compounds were prepared by the same manner as in ReferenceExample 20.

Reference Example 21

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(2,4-difluorophenyl)-2(1H,3H)-imidazolone.

Colorless powdery crystals; yield: 416 mg (66%).

mp 134°-136° C.

¹ H-NMR (CDCl₃) δ: 1.21 (3H,d,J=7 Hz), 4.19 (1H,d,J=14.4 Hz), 4.95(1H,q,J=7 Hz), 5.11 (1H,d,J=14.4 Hz), 5.52 (1H,br), 6.52 (1H,t,J=2.6Hz), 6.70-6.86 (3H,m), 6.92-7.06 (2H,m), 7.40-7.68 (2H,m), 7.74 (1H,s),7.85 (1H,s).

Reference Example 22

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethoxyphenyl)-2(1H,3H)-imidazolone.

Colorless powder; yield: 500 mg (71%).

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.19 (1H,d,J=14.4 Hz), 4.97(1H,q,J=7 Hz), 5.10 (1H,d,J=14.4 Hz), 5.51 (1H,br), 6.39 (1H,d,J=3.2Hz), 6.64 (1H,d,J=3.2 Hz), 6.70-6.86 (2H,m), 7.31 (2H,d,J=9 Hz),7.38-7.54 (1H,m), 7.69 (2H,d,J=9 Hz), 7.74 (1H,s), 7.84 (1H,s).

Reference Example 23

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-fluorophenyl)-2(1H,3H)-imidazolone.

Colorless powder; yield: 971 mg (74%).

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.20 (1H,d,J=14.2 Hz), 4.95(1H,q,J=7 Hz), 5.10 (1H,d,J=14.2 Hz), 5.58 (1H,br), 6.60 (1H,d,J=3.2Hz), 6.74 (1H,d,J=3.2 Hz), 6.70-6.88 (2H,m), 7.05-7.20 (2H,m), 7.40-7.65(3H,m), 7.73 (1H,s), 7.85 (1H,s).

Reference Example 24

To a solution of 1.36 g of(1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol in 30 ml ofdichloromethane was added 1.31 ml of diisopropylethylamine at -60° C.under an atmosphere of nitrogen and then 1.26 ml oftrifluoromethanesulfonic acid anhydride was added dropwise thereintoover the period of three minutes. The mixture was stirred at -60° C. for20 minutes, then at -20° C. for 20 minutes. The reaction solution wassubjected to flush chromatography using 27 g of silica gel and elutedwith 220 ml of dichloromethane-hexane (1:1). The fraction containing theproduct was concentrated to about 9 ml and the residue was added to amixture of 1.15 g of 3-(2,4-difluorophenyl)-2,4-imidazolidinedione, 18ml of dimethylformamide and 0.20 g of 60% sodium hydride in oil at -10°C. The resulting mixture was stirred for 20 minutes and then for 20minutes at 0° C. Water (20 ml) was added thereto and the mixture wasextracted with 100 ml of ethyl acetate. The ethyl acetate layer waswashed with 20 ml of a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and distilled off under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane/ethyl acetate=2/1) to give 1.25 g of1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(2,4-difluorophenyl)-2,4-imidazolidinedioneas a white solid.

mp 124°-125° C. (recrystallized from ethyl acetatehexane).

¹ H-NHR (CDCl₃) δ: 1.30 (3H,d,J=7.2 Hz), 2.81 (1H,d,J=4.6 Hz), 3.08(1H,d,J=4.6 Hz), 4.06 (1H,d,J=17.8 Hz), 4.22 (1H,d,J=17.8 Hz), 4.97(1H,q,J=7.2 Hz), 6.78-7.04 (4H,m), 7.20-7.45 (2H,m).

Reference Examples 25-29

The following compounds were prepared by the same manner as in ReferenceExample 24.

Reference Example 25

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone.

Colorless powder.

¹ H-NMR (CDCl₃) δ: 1.21 (3H,d,J=7.2 Hz), 2.75 (1H,d,J=7.0 Hz), 3.15(1H,d,J=7.0 Hz), 3.42-3.64 (2H,m), 3.71-3.81 (2H,m), 4.32 (2H,tt,J=12Hz,1.4 Hz), 4.80 (1H,q,J=7.2 Hz), 6.06 (1H,tt,J=53 Hz,5 Hz), 6.76-6.9(2H,m), 6.91 (2H,d,J=9.2 Hz), 7.35-7.5 (1H,m), 7.48 (2H,d,J=9.2 Hz).

Reference Example 26

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxyphenyl]-2-imidazolidinone.

Colorless powder.

¹ H-NMR (CDCl₃) δ: 1.22 (3H,d,J=7.4 Hz), 2.75 (1H,d,J=5 Hz), 3.14(1H,d,J=5 Hz), 3.44-3.65 (2H,m), 3.73-3.84 (2H,m), 4.80 (1H,q,J=7.4 Hz),5.89 (1H,tt,J=53 Hz,2.8 Hz), 6.77-6.93 (2H,m), 7.17 (2H,d,J=9 Hz),7.34-7.46 (1H,m), 7.55 (2H,d,J=9 Hz). IR (KBr) ν_(max) : 1680, 1615,1510, 1485, 1425 (cm⁻¹).

Reference Example 27

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2-imidazolidinone.

Colorless prisms.

mp 141°-144° C. (ethyl acetate-hexane).

¹ H-NMR (CDCl₃) δ: 1.22 (3H,d,J=7 Hz), 2.75 (1H,d,J=5.0 Hz), 3.15(1H,d,J=5.0 Hz), 3.42-3.64 (2H,m), 3.73-3.82 (2H,m), 4.39 (2H,dt,J=12.4Hz,1.2 Hz), 4.80 (1H,q,J=7 Hz), 6.77-6.90 (2H,m), 6.92 (1H,d,J=9.2 Hz),7.34-7.42 (1H,m), 7.48 (2H,d,J=9.2 Hz).

Elemental analysis for C₂₂ H₁₉ F₇ N₂ O₃ Calcd (%): C 53.66, H 3.89, N5.69 Found (%): C 53.37, H 3.74, N 5.62

IR (KBr).sub.νmax : 1700, 1520, 1485, 1430, 1265 (cm⁻¹).

Reference Example 28

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-imidazolidinone.

Colorless needles.

mp 131°-132° C. (diethyl ether).

¹ H-NMR (CDCl₃) δ: 1.21 (3H,d,J=7.2 Hz), 2.75 (1H,d,J=5 Hz), 3.15(1H,d,J=5 Hz), 3.42-3.64 (2H,m) , 3.73-3.82 (2H,m), 4.32 (2H,q,J=8.2Hz), 4.80 (1H,q,J=7.2 Hz), 6.77-6.88 (2H,m), 6.92 (2H,d,J=9 Hz),7.34-7.44 (1H,m), 7.48 (2H,d,J=9 Hz).

Elemental analysis for C₂₁ H₁₉ F₅ NO₃ Calcd (%): C 57.02, H 4.33, N 6.33Found (%): C 57.33, H 4.06, N 6.39

IR (KBr) .sub.νmax : 1695, 1515, 1485, 1425, 1265, 1240 (cm⁻¹).

Reference Example 29

1-(4-Chlorophenyl)-3-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-imidazolidinone.

Colorless needles.

mp 130°-131° C. (ethyl acetate-hexane).

¹ H-NMR (CDCl₃) δ: 1.22 (3H,d,J=7 Hz), 2.75 (1H, d, J=5 Hz), 3.14(1H,d,J=5 Hz), 3.43-3.65 (2H,m), 3.73-3.82 (2H,m), 4.80 (1H,q,J=7 Hz),6.77-6.93 (2H,m), 7.28 (2H,d,J=9 Hz), 7.34-7.54 (1H,m), 7.49 (2H,d,J=9Hz).

Elemental analysis for C₁₉ H₁₇ ClF₂ N₂ O₂ Calcd (%): C 60.24, H 4.52, N7.40 Found (%): C 60.45, H 4.38, N 7.45

IR (KBr) .sub.νmax : 1700, 1615, 1600, 1500, 1425, 1270 (cm⁻¹).

Reference Example 30

A mixture of 8.6 g of 4-(2,2,3,3-tetrafluoropropoxy)aniline, 4.8 g ofethyl chloroacetate, 4.8 g of sodium bicarbonate, 3.0 g of sodium iodideand 300 ml of acetone was refluxed for 21 hours. The solvent wasdistilled off under reduced pressure and 200 ml of ice water and 200 mlof dichloromethane were added to the residue to fractionate. Thedichloromethane layer was washed with water, dried over anhydrousmagnesium sulfate and distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (eluted with ethylacetate:hexane [1:3 v/v]) to give 9.4 g ofN-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline as paleyellow crystals.

To a mixture of 2.1 g of the resultingN-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline, 1.1 ml oftriethylamine and 50 ml of dichloromethane was added dropwise a solutionof 0.6 ml of chloroacetyl chloride in 6 ml of dichloromethane with icecooling and the resulting mixture was stirred at room temperature forfive hours. To the reaction solution was added 50 ml of dichloromethaneand 100 ml of ice water to factionate. The dichloromethane layer waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure and the residue waspurified by silica gel column chromatography (eluted with ethylacetate:hexane [1:2 v/v]) to give 2.4 g ofN-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)anilineas a yellow oily substance.

The resultingN-chloroacetyl-N-ethoxycarbonylmethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline(1.9 g) was dissolved in 20 ml of 10.5% ammonia-ethanol and the solutionwas stirred at 60° C. for four hours. After cooling, the crystalsseparated out therefrom were collected by filtration and washed withcold ethanol to give 1.5 g of1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione ascolorless crystals.

¹ H-NMR (d₆ -DMSO) δ: 3.95 (2H,s), 4.20 (2H,s), 4.60 (2H,t,J=14 Hz),6.67 (1H,tt,J=52 Hz,5.4 Hz), 7.08 (2H,d,J=9 Hz), 7.30 (2H,d,J=9 Hz),8.27 (1H, brs).

Elemental analysis for C₁₃ H₁₂ F₄ N₂ O₃ Calcd (%): C 48.76, H 3.78, N8.75 Found (%): C 48.99, H 3.65, N 8.88.

SIMS (MH⁺): 321.

IR (KBr) .sub.νmax : 3440, 3250, 1670, 1650, 1510, 1330 (cm⁻¹).

Reference Example 31

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedionewas obtained by the same manner as in Reference Example 24.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.25 (3H,d,J=7.2 Hz), 2.85 (1H,d,J=5 Hz) 3.10(1H,d,J=5 Hz), 4.07 (1H,d,J=17 Hz), 4.21 (1H,d,J=17 Hz), 4.23 (1H,d,J=16Hz), 4.34 (1H,d,J=16 Hz), 4.36 (2H,t,J=12 Hz), 5.37 (1H,q,J=7.2 Hz),6.06 (1H,tt,J=53 Hz,4.8 Hz), 6.78-6.95 (2H,m), 6.98 (2H,d,J=9 Hz), 7.23(2H,d,J=9 Hz), 7.35-7.47 (1H,m).

mp 155°-156° C. (ethyl acetate-hexane).

Elemental analysis for C₂₃ H₂₀ F₆ N₂ O₄ Calcd (%): C 54.99, H 4.01, N5.58 Found (%): C 54.77, H 4.03, N 5.36

Reference Example 32

1-(4-Trifluoromethylphenyl)-2(1H,3H)-imidazolone (1.15 g) was dissolvedin 20 ml of acetic acid. 10% Palladium-carbon (0.3 g) was added theretoand the mixture was stirred under a hydrogen stream for six hours. Thecatalyst was filtered off, the solvent was distilled off and the residuewas recrystallized from ethyl acetate-diisopropyl ether to give 0.95 gof 1-(4-trifluoromethylphenyl)-2-imidazolidinone as colorless prisms.

mp 169°-171° C. (ethyl acetate-diisopropyl ether).

¹ H-NMR (CDCl₃) δ: 3.63 (2H,t,J=8 Hz), 3.99 (2H,t,J=8 Hz), 4.95 (1H,br),7.59 (2H,d,J=9 Hz), 7.68 (2H,d,J=9 Hz).

Elemental analysis for C₁₀ H₉ F₃ N₂ O Calcd (%): C 52.18, H 3.94, N12.17 Found (%): C 51.94, H 3.89, N 12.23

Reference Example 33

1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2-imidazolidinonewas obtained as a colorless powder by the same manner as in ReferenceExample 24.

¹ H-NMR (CDCl₃) δ: 1.24 (3H,d,J=7.2 Hz), 2.76 (1H,d,J=4.8 Hz), 3.14(1H,d,J=4.8 Hz), 3.48-3.70 (2H,m), 3.78-3.90 (2H,m), 4.83 (1H,q,J=7.2Hz), 6.78-6.95 (2H,m), 7.35-7.48 (1H,m), 7.57 (2H,d,J=8.8 Hz), 7.67(2H,d,J=8.8 Hz).

Reference Example 34

In the same manner as in Reference Example 30, starting from4-(1,1,2,2-tetrafluoroethoxy)aniline,1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,5-piperazinedione was obtainedas colorless crystals.

¹ H-NMR (DMSO-d₆) δ: 3.97 (2H,s), 4.27 (2H,s), 6.81 (1H,tt,J=52 Hz,3Hz), 7.32 (2H,d,J=9 Hz), 7.46 (2H,d,J=9 Hz), 8.31 (1H,br).

mp >250° C.

Elemental analysis for C₁₂ H₁₀ F₄ N₂ O₃ Calcd (%): C 47.07, H 3.29, N9.15 Found (%): C 46.89, H 3.26, N 9.08

Reference Example 35

In the same manner as in Reference Example 24,1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,5-piperazinedionewas obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.25 (3H,d,J=7 Hz), 2.85 (1H,d,J=5 Hz), 3.09(1H,d,J=5 Hz), 4.08 (1H,d,J=17 Hz), 4.22 (1H,d,J=17 Hz), 4.26 (1H,d,J=16Hz), 4.37 (1H,d,J=16 Hz), 5.36 (1H,q,J=7 Hz), 5.92 (1H,tt,J=53 Hz,3 Hz),6.78-6.95 (2H,m), 7.29 (4H,s), 7.30-7.47 (1H,m).

mp 168°-170° C.

Elemental analysis for C₂₂ H₁₈ F₆ N₂ O₄ Calcd (%): C 54.11, H 3.71, N5.74 Found (%): C 54.08, H 3.75, N 5.64

Reference Example 36

A mixture of 4-(2,2,3,3-tetrafluoropropoxy)aniline (7.4 g),N-(2-bromoethyl)phthalimide (9.0 g), potassium bicarbonate (6.9 g),potassium iodide (5.5 g) and N,N-dimethylformamide (80 ml) are refluxedfor 22 hours. The solvent was distilled off under reduced pressure. Tothe residue, ice-water (200 ml) and ethyl acetate (200 ml) were addedand fractionated. The ethyl acetate layer was washed with water, driedover anhydrous magnesium sulfate and distilled off under reducedpressure. The residue was purified by silica gel chromatography (eluate;ethyl acetate:hexane=1:2 v/v) and recrystallized from ethylacetate-diisopropyl ether to giveN-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (5.4 g) aswhite crystals.

To the mixture of the obtainedN-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.2 g),triethylamine (1.2 ml) and dichloromethane (60 ml), was added dropwise asolution of ethyl chloroglyoxylate (0.9 ml) in dichloromethane (10 ml)at -65° C. The reaction solution was stirred for 1 hour at -40° C., andthen ice-water (50 ml) was added thereto to fractionate. Thedichloromethane layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to giveN-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline(3.1 g) as colorless powdery crystals.

The mixture of the obtainedN-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline(3.4 g), hydradine hydrate (0.7 ml) and ethanol (80 ml) was refluxed for9 hours. The crystals separated out were filtered off before cooling andthe solvent of the filtrate was distilled off under reduced pressure.Water (150 ml) and ethyl acetate (300 ml) were added to the residue tofractionate. The ethyl acetate layer was washed with 5% aqueous solutionof sodium bicarbonate and then with a saturated aqueous solution ofsodium chloride, and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure. The residue was purified bysilica gel chromatography (eluent; ethylacetate:dichloromethane:methanol=7:7:1 v/v) to give1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedione (0.8 g) asa colorless powder.

¹ H-NMR (DMSO-d₆) δ: 3.44-3.55 (2H,m), 3.83-3.89 (2H,m), 4.61 (2H,t,J=13Hz), 6.68 (1H,tt,J=52 Hz,6 Hz), 7.09 (2H,d,J=9 Hz), 7.34 (2H,d,J=9 Hz),8.73 (1H,br).

Elemental analysis for C₁₃ H₁₂ F₄ N₂ O₃ Calcd (%): C 48.76, H 3.78, N8.75 Found (%): C 48.44, H 3.62, N 8.73 SIMS (MH⁺): 321

Reference Example 37

In the same manner as in Reference Example 24,1-(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedionewas obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.26 (3H,d,J=7 Hz), 2.81 (1H,d,J=5 Hz), 3.13(1H,d,J=5 Hz), 3.61-3.81 (3H,m), 3.90-4.04 (1H,m), 4.36 (2H,t,J=12 Hz),5.40 (1H,q,J=7 Hz), 6.06 (1H,tt,J=53 Hz,5 Hz), 6.80-6.95 (2H,m), 6.97(2H,d,J=9 Hz), 7.32 (2H,d,J=9 Hz), 7.35-7.47 (1H,m).

Elemental analysis for C₂₃ H₂₀ F₆ N₂ O₄ Calcd (%): C 54.99, H 4.01, N5.58 Found (%): C 54.61, H 4.01, N 5.65

mp 197°-201° C.

Reference Example 38

In the same manner as in Reference Example 36, starting from4-(1,1,2,2-tetrafluoroethoxy)aniline,1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,3-piperazinedione wasobtained.

Colorless powdery crystals.

¹ H-NMR (DMSO-d₆) δ: 3.46-3.53 (2H,m), 3.90-3.96 (2H,m), 6.81(1H,tt,J=52 Hz,3 Hz), 7.33 (2H,d,J=9 Hz), 7.50 (2H,d,J=9 Hz), 8.78(1H,br).

Elemental analysis for C₁₂ H₁₀ F₄ N₂ O₃ Calcd (%): C 47.07, H 3.29, N9.15 Found (%): C 46.86, H 3.24, N 9.11

mp 240°-242° C.

Reference Example 39

In the same manner as in Reference Example 24,1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,3-piperazinedionewas obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.25 (3H,d,J=7 Hz), 2.80 (1H,d,J=5 Hz), 3.13(tH,d,J=5 Hz), 3.60-3.85 (3H,m), 3.95-4.08 (1H,m), 5.37 (1H,q,J=7 Hz),5.92 (1H,tt,J=53 Hz,3 Hz), 6.81-6.93 (2H,m), 7.25 (2H,d,J=8 Hz),7.34-7.45 (3H,m).

mp 214°-215° C.

Elemental analysis for C₂₂ H₁₈ F₆ N₂ O₄ Calcd (%): C 54.11, H 3.71, N5.74 Found (%): C 53.88, H 3.68, N 5.72

Reference Example 40

In the same manner as in Reference Example 1, starting from2-(2-fluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane(synthesized by the method described in EP 0548553A),[(1R)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoatewas obtained.

Colorless prisms (recrystallized from ethyl acetate)

mp 183°-184 ° C.

¹ H-NMR (CDCl₃) δ: 1.47 (3H,dd,J=6.6 Hz,l.6 Hz), 3.03 (1H,d,J=4.7 Hz),3.23 (1H, d, J=4.7 Hz), 5.35 (1H, q, J=6.6 Hz), 7.09-7.59 (4H,m), 9.13(2H,t,J=2.2 Hz), 9.23 (1H,t,J=2.2 Hz).

[α]_(D) ²³ -24.7° C. (C=1.0, CHCl₃)

Elemental analysis for C₁₇ H₁₃ FN₂ O₇ Calcd (%): C 54.26, H 3.48, N 7.44Found (%): C 54.23, H 3.25, N 7.41

Reference Example 41

In the same manner as in Reference Example 3, starting from[(1R)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoate,(1R)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol was obtained.

Colorless oily substance.

¹ H-NMR (CDCl₃) δ: 1.17 (3H,dd,J=6.6 Hz,1.0 Hz), 1.78 (1H,d,J=8.2 Hz),2.81 (1H,d,J=5.3 Hz), 3.32 (1H,d,J=5.3 Hz), 4.15 (1H,m), 6.99-7.47(4H,m).

Reference Example 42

In the same manner as in Reference Example 4, starting from(1R)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol,(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol was obtained.

Colorless oily substance.

¹ H-NMR (CDCl₃) δ: 1.21 (3H,d,J=7 Hz), 2.27 (1H,d,J=2 Hz), 2.96(1H,d,J=5 Hz), 3.30 (1H,d,J=5 Hz), 4.16 (1H,dd,J=7 Hz, 2 Hz), 7.03-7.44(4H,m).

Reference Example 43

In the same manner as in Reference Example 24,1-[(1R,2S)-2,3-epoxy-2-(2-fluorophenyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinonewas obtained.

Colorless powdery crystals (recrystallized from diisopropyl ether)

mp 148°-149° C.

¹ H-NMR (CDCl₃) δ: 1.24 (3H,d,J=7.2 Hz), 2.78 (1H,d,J=5.0 Hz), 3.15(1H,d,J=5.0 Hz), 3.45-3.84 (4H,m), 4.85 (1H,q,J=7.2 Hz), 5.90(1H,tt,J=53.2 Hz,2.8 Hz), 7.02-7.60 (8H,m).

Elemental analysis for C₂₁ H₁₉ F₅ N₂ O₃ Calcd (%): C 57.02, H 4.33, N6.33 Found (%): C 56.90, H 4.36, N 6.31

Reference Example 44

In the same manner as in Reference Example 24,1-[(1R,2S)-2,3-epoxy-2-(2-fluorophenyl)-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinonewas obtained.

Colorless powdery crystals (recrystallized from diisopropyl ether)

mp 144°-145° C.

¹ H-NMR (CDCl₃) δ: 1.22 (3H,d,J=7.4 Hz), 2.77 (1H,d,J=5.0 Hz), 3.16(1H,d,J=5.0 Hz), 3.47-3.77 (4H,m), 4.32 (2H,tt,J=12 Hz,1.6 Hz), 4.85(1H,q,J=7.4 Hz), 6.07 (1H,tt,J=53 Hz,5 Hz), 6,89-7.52 (8H,m).

Elemental analysis for C₂₂ H₂₁ F₅ N₂ O₃ Calcd (%): C 57.90, H 4.64, N6.14 Found (%): C 57.94, H 4.60, N 6.19

Reference Example 45

(2R,3S)-2-(4-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane(1.5 g), 2.66 g of1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 6.3 gof cesium carbonate were added to 25 ml of N,N-dimethylformamide. Themixture was stirred at 80° C. for five hours. After cooling, thereaction solution was diluted with 100 ml of ethyl acetate, and washedwith water (100 ml×2) and a saturated aqueous solution of sodiumchloride (100 ml) successively. The ethyl acetate layer was dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by silica gel chromatography(eluent: hexane/ethyl acetate=2/3) to give 1.21 g of1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazoloneas colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7.2 Hz), 4.19 (1H,d,J=14 Hz), 4.70(1H,d,J=14 Hz), 4.79 (1H,q,J=7.2 Hz), 5.34-5.39 (1H,bs), 5.92(1H,tt,J=2.SHz,53 Hz), 6.63 (1H,d,J=3 Hz), 6.78 (1H,d,J=3 Hz), 6.94-7.03(2H,m), 7.28-7.39 (4H,m), 7.66 (2H,d,J=9 Hz), 7.69 (1H,s), 7.78 (1H,s).

Reference Example 46

In the same manner as in Reference Example 45,1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolonewas obtained.

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.20 (1H,d,J=14 Hz), 4.41(2H,t,J=12 Hz), 4.68-4.80 (2H,m), 5.42-5.48 (1H,bs), 6.07 (1H,tt,J=5Hz,53 Hz), 6.59 (1H,d,J=3 Hz), 6.76 (1H,d,J=3 Hz), 6.92-7.04 (2H,m),7.30-7.39 (4H,m), 7.58 (2H,d,J=9 Hz), 7.66 (1H,s), 7.78 (1H,s).

Reference Example 47

In the same manner as in Reference Example 45,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolonewas obtained.

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.19 (1H,d,J=14 Hz), 4.97(1H,q,J=7 Hz), 5.10 (1H,d,J=14 Hz), 5.41-5.59 (1H,br), 5.93 (1H,tt,J=53Hz,2.8 Hz), 6.64 (1H,d,J=3 Hz), 6.77 (1H,d,J=3 Hz), 6.74-6.87 (2H,m),7.30 (2H,d,J=9 Hz 7.40-7.56 (1H,m), 7.66 (2H,d,9 Hz), 7.74 (1H,s), 7.85(1H,s).

Reference Example 48

In the same manner as in Reference Example 45,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone was obtained.

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.20 (1H,d,J=14 Hz), 4.37(2H,t,J=12 Hz), 4.94 (1H,q,J=7 Hz), 5.09 (1H,d,J=14 Hz), 5.54-5.75(1H,br), 6.06 (1H,tt,J=53 Hz,5 Hz), 6.59 (1H,d,J=3 Hz), 6.72 (1H,d,J=3Hz), 6.74-6.86 (2H,m), 7.00 (2H,d,J=9 Hz), 7.42-7.55 (1H,m), 7.57(2H,d,9 Hz), 7.72 (1H,s), 7.85 (1H,s).

Reference Example 49

(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane(1.5 g), 2.66 g of1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone and 0.386 gof 60% sodium hydride in oil were added to 25 ml ofN,N-dimethylformamide. The mixture was stirred at 80° C. for 20 hours.After cooling, the reaction mixture was added to 100 ml of water andextracted with ethyl acetate (50 ml×2). The extract was washed withwater, dried over anhydrous magnesium sulfate and then distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=3/2) to give 0.27 g of1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazoloneas a colorless powder.

Elemental analysis for C₂₃ H₂₀ F₅ N₅ O₃ Calcd (%): C 54.23, H 3.96, N13.75 Found (%): C 53.83, H 3.99, N 13.56

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.20 (1H,d,J=14 Hz), 5.05(1H,q,J=7 Hz), 5.16 (1H,d,J=14 Hz), 5.30-5.41 (1H,br), 5.93 (1H,tt,J=53Hz,2.8 Hz), 6.65 (1H,d,J=3 Hz), 6.81 (1H,d,J=3 Hz), 6.98-7.08 (2H,m),7.18-7.51 (2H,m), 7.30 (2H,d,J=9 Hz), 7.70 (2H,d,J=9 Hz), 7.73 (1H,s),7.81 (1H,s).

Reference Example 50

In the same manner as in Reference Example 20, starting from(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol, the followingcompounds were obtained.

1-[(1R,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone:

Colorless powdery crystals (recrystallized from diisopropyl ether)

mp 118°-119° C.

¹ H-NMR (CDCl₃) δ: 1.37 (3H,d,J=7 Hz), 2.72 (1H,d,J=5 Hz), 2.81(1H,d,J=5 Hz), 4.36 (2H,tt,J=12 Hz,2 Hz), 5.12 (1H,q,J=7 Hz), 6.07(1H,tt,J=53 Hz,5 Hz), 6.45(1H,d,J=3 Hz), 6.51 (1H,d,J=3 Hz), 6.98(2H,d,J=9 Hz), 7.04-7.19 (2H,m), 7.28-7.47 (2H,m), 7.57 (2H,d,J=9 Hz).

1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone:

Colorless powdery crystals

Elemental analysis for C₂₄ H₂₂ F₅ N₅ O₃ Calcd (%): C 55.07, H 4.24, N13.38 Found (%): C 54.98, H 4.18, N 13.35

¹ H-NMR (CDCl₃) δ: 1.20 (3H,d,J=7 Hz), 4.21 (1H,d,J=14 Hz), 4.37(2H,t,J=12 Hz), 4.95-5.11 (1H,m), 5.15 (1H,d,J=14 Hz), 5.34-5.56(1H,br), 6.07 (1H, tt, J=53 Hz, 5 Hz), 6.59 (1H,d,J=3 Hz), 6.76(1H,d,J=3 Hz), 6.97-7.07 (2H,m), 7.01 (2H,d,J=9 Hz), 7.17-7.29 (1H,m),7.44-7.52 (1H,m), 7.59 (2H,d,J=9 Hz), 7.72 (1H,s), 7.82 (1H,s).

Reference Example 51

In the same manner as in Reference Example 1, starting from2-(2-fluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane(synthesized by the method described in EP 0548553A),(1R)-1-[2-(2-fluorophenyl)-2-oxiranyl]ethanol was obtained. To asolution of this product (34.77 g) in tetrahydrofuran (600 ml) wereadded, with ice cooling, 127.21 g of triphenyl phosphine, 102.88 g of3,5-dinitrobenzoic acid and 84.47 g of diethyl azodicarboxylate, and theresulting mixture was stirred at room temperature for 7 hours under anatmosphere of argon. To the reaction solution were added 600 ml of ethylacetate, 100 ml of diisopropyl ether and 800 ml of water to fractionateand the aqueous layer was extracted with ethyl acetate (600 ml, 400 ml).The organic layers were combined, washed with water and a saturatedaqueous solution of sodium chloride successively, then dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (eluent: hexane/ethyl acetate=5/1)to give 23.15 g of[(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl)ethyl]3,5-dinitrobenzoate ascolorless needles.

¹ H-NMR (CDCl₃) δ: 1.47 (3H,d,J=7 Hz), 2.97 (1H,d,J=5 Hz), 3.29(1H,d,J=5 Hz), 5.43 (1H,q,J=7 Hz), 7.02-7.56 (4H,m), 9.06 (2H,d,J=2 Hz),9.21 (1H,t,J=2 Hz).

This product (22.91 g) was dissolved in 700 ml of methanol and, with icecooling, 146.5 ml of 1N sodium hydroxide was added thereto. The reactionsolution was stirred at room temperature for one hour. To the reactionsolution was added 85.5 ml of 1N hydrochloric acid and the solvent wasdistilled off under reduced pressure. Ethyl acetate (500 ml) and water(500 ml) were added to the residue to fractionate. The organic layer waswashed with water and a saturated aqueous solution of sodium chloridesuccessively, then dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=3/1) to give 10.76 g of(1S)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol as a colorless oilysubstance. This product was identical with the compound obtained inReference Example 42.

Reference Example 52

60% Sodium hydride in oil (2.4 g) was added portionwise to a stirredsolution of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone(16.6 g) and the resulting mixture was stirred for 30 minutes at roomtemperature.(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane(10 g) was added and the mixture was stirred at 80° C. for 20 hours.After cooling, the mixture was concentrated into a volume of about 50 mlunder reduced pressure and diluted ice-water (400 ml) and ethyl acetate(500 ml). The ethyl acetate layer was separated, washed with a 10%aqueous phosphoric acid solution (400 ml) and an aqueous solution ofsodium chloride (400 ml×2) successively and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue was purified by silica gel column chromatography(eluent: hexane/ethyl acetate=1/1 to 2/1) to give1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone(7.56 g) as an oily substance, which was identical with the compoundobtained in the Reference Example 47.

Working Example 1

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethoxyphenyl)-2(1H,3H)-imidazolone(100 mg) obtained in Reference Example 22 was dissolved in 10 ml ofacetic acid, 50 mg of 10% palladium-carbon was added thereto and themixture was stirred under an atmosphere of hydrogen at room temperaturefor eight hours. The catalyst was filtered off and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1/5) to give 66 mg of1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethoxyphenyl)-2-imidazolidinone(Compound 1) 4.53 (1H,d,J=14.2 Hz), 4.60-4.80 (1H,m), 5.10 (1H,d,J=14.2Hz), 5.40 (1H,br), 6.68-6.85 (2H,m) 7.31 (2H, d,J=9 Hz), 7.32-7.48(1H,m), 7.69 (2H,d,J=9 Hz), 7.76 (1H,s), 7.88 (1H,s).

Working Example 2

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(2,4-difluorophenyl)-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(2,4-difluorophenyl)-2-imidazolidinone(Compound 2) was obtained.

Colorless powder.

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 3.65-4.05 (4H,m), 4.55(1H,d,J=14.2 Hz), 4.45-4.65 (1H,m), 5.10 (1H,d,J=14.2 Hz), 5.60 (1H,br),6.68-7.02 (4H,m), 7.36-7.68 (2H,m), 7.76 (1H,s), 7.93 (1H,s).

Working Example 3

A mixture of 0.41 g of 1H-1,2,4-triazole, 0.19 g of 60% sodium hydridein oil and 12 ml of dimethylformamide was stirred at room temperaturefor 20 minutes, 0.85 g of1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(2,4-difluorophenyl)-2,4-imidazolidinedioneobtained in Reference Example 24 was added thereto and the mixture washeated at 60° C. for four hours. After cooling, 20 ml of water was addedto the reaction solution and the mixture was extracted with 80 ml ofethyl acetate. The extract was washed with 20 ml of a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (eluent: hexane/ethyl acetate=1/2 to 1/5) to give0.12 g of1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(2,4-difluorophenyl)-2,4-imidazolidinedione(Compound 3) as a colorless powder.

¹ H-NMR (CDCl₃) δ: 1.10 (3H,d,J=7 Hz), 4.25 (1H,d,J=18 Hz), 4.41(1H,d,J=14.2 Hz), 4.67 (1H,d,J=18 Hz), 4.94 (1H, dq,J=1.6 Hz,J=7 Hz),5.15 (1H,d,J=14.2 Hz), 5.35 (1H,d,J=1.6 Hz), 6.70-6.84 (2H,m), 6.94-7.06(2H,m), 7.27-7.44 (2H,m), 7.80 (1H,s), 7.82 (1H,s).

Working Example 4

(Method A)

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethylphenyl)-2-imidazolidinone(Compound 4) was obtained.

(Method B)

The same reaction as in Working Example 3 was carried out using1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2-imidazolidinoneobtained in Reference Example 33 to give1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethylphenyl)-2-imidazolidinone(Compound 4) as a colorless powder.

Elemental analysis for C₂₂ H₂₀ F₅ N₅ O₂ Calcd (%): C 54.89, H 4.19, N14.55 Found (%): C 54.72, N 4.19, N 14.29

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 3.60-4.12 (4H, m), 4.49(1H,d,J=14.2 Hz), 4.60-4.80 (1H,m), 5.11 (1H,d,J=14.2 Hz), 5.36 (1H,br),6.70-6.85 (2H,m), 7.32-7.48 (1H,m), 7.60 (2H,d,J=8.8 Hz), 7.70(1H,d,J=8.8 Hz), 7.76 (1H,s), 7.85 (1H,s).

Working Example 5

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-fluorophenyl)-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-fluorophenyl)-2-imidazolidinone(Compound 5) was obtained.

Colorless powdery crystals.

mp 74°-78° C. (ethyl acetate-hexane)

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.0 Hz), 3.65-3.73 (1H, m), 3.79-4.00(3H,m), 4.51 (1H,d,J=14 Hz), 4.60 (1H,m), 5.07 (1H,d,J=14 Hz), 5.3-5.7(1H,br), 6.71-6.82 (2H,m), 6.99-7.11 (2H,m), 7.36-7.56 (3H,m), 7.74(1H,s), 7.87 (1H,s).

IR (KBr) .sub.νmax : 3420, 1690, 1615, 1510, 1480, 1420 (cm⁻¹)

Working Example 6

(Method A)

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone(Compound 6) was obtained.

(Method B)

In the same manner as in Working Example 3, starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone(Compound 6) was obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.0 Hz), 3.66-3.73 (1H, m), 3.80-3.95(3H,m), 4.33 (2H,tt,J=12 Hz,1.6 Hz), 4.52 (1H, d,J=14.4 Hz), 4.5-4.65(1H,m), 5.08 (1H,d,J=14.4 Hz), 5.45-5.65 (1H,br), 6.06 (1H,tt,J=53Hz,4.8 Hz), 6.70-6.83 (2H,m), 6.94 (2H,d,J=9.2 Hz), 7.39-7.54 (1H,m),7.50 (2H,d,J=9.2 Hz), 7.74 (1H,s), 7.88 (1H,s).

Elemental analysis for C₂₄ H₂₃ F₆ N₅ O₃ Calcd (%): C 53.04, H 4.27, N12.89 Found (%): C 53.04, H 4.50, N 12.82

IR (KBr) .sub.νmax : 3380, 1690, 1665, 1510, 1485, 1440 (cm⁻¹).

Working Example 7

(Method A)

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone(Compound 7) was obtained.

(Method B)

In the same manner as in Working Example 3, starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone(Compound 7) was obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 3.67-3.75 (1H,m), 3.82-4.01(3H,m), 4.50 (1H,d,J=15 Hz), 4.65 (1H,m), 5.10 (1H, d,J=15 Hz), 5.3-5.6(1H,br), 5.91 (1H,tt,J=53 Hz,3.0 Hz), 6.72-6.83 (2H,m), 7.21 (2H,d,J=9.2Hz), 7.36-7.49 (1H,m), 7.58 (2H,d,J=9.2 Hz), 7.75 (1H,s), 7.86 (1H,s).

Elemental analysis for C₂₃ H₂₁ F₆ N₅ O₃ Calcd (%): C 52.18, N 4.00, N13.23 Found (%): C 52.30, H 3.95, N 13.28

IR (KBr) .sub.νmax : 3380, 1680, 1615, 1510, 1480, 1425 (cm⁻¹).

Working Example 8-14

In the same manner as in Working Example 3, the following compounds wereobtained.

Working Example 8

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-2-imidazolidinone(Compound 8) was obtained.

Colorless powder.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.2 Hz), 3.66-3.73 (1H, m), 3.79-4.01(3H,m), 4.41 (2H,t,J=12.4 Hz), 4.52 (1H,d,J=14 Hz), 4.51-4.68 (1H,m),5.08 (1H,d,J=14 Hz), 5.3-5.8 (1H,br), 6.71-6.82 (2H,m), 6.96 (2H,d,J=9.2Hz), 7.37-7.5 (1H,m), 7.51 (2H,d,J=9.2 Hz), 7.74 (1H,s), 7.88 (1H,s).

Elemental analysis for C₂₄ H₂₂ F₇ N₅ O₃ Calcd (%): C 51.34, H 3.95, N12.47 Found (%): C 51.14, H 3.95, N 12.32

IR (KBr) .sub.νmax : 3420, 1690, 1610, 1510, 1480, 1425 (cm⁻¹).

Working Example 9

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-imidazolidinone(Compound 9) was obtained.

Colorless powdery crystals.

mp 80°-83° C. (diethyl ether)

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.2 Hz), 3.65-3.74 (1H, m), 3.79-3.95(3H,m), 4.34 (2H,q,J=8 Hz), 4.52 (1H,d,J=14 Hz), 4.5-4.65 (1H,m), 5.08(1H,d,J=14 Hz), 5.4-5.7 (1H,br), 6.71-6.81 (2H,m), 6.96 (2H,d,J=9.2 Hz),7.38-7.5 (1H,m), 7.50 (2H, d,J=9.2 Hz), 7.74 (1H,s), 7.88 (1H,s).

Elemental analysis for C₂₃ H₂₂ F₅ N₅ O₃ Calcd (%): C 54.01, H 4.34, N13.69 Found (%): C 53.67, H 4.27, N 13.79

IR (KBr) .sub.νmax : 3410, 1690, 1610, 1510, 1480, 1420 (cm⁻¹).

Working Example 10

Starting from1-(4-chlorophenyl)-3-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-imidazolidinone,1-(4-chlorophenyl)-3-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-2-imidazolidinone(Compound 10) was obtained.

Colorless powdery crystals.

mp 138°-139° C. (diethyl ether-hexane).

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.0 Hz), 3.64-3.75 (1H, m), 3.80-4.03(3H,m), 4.50 (1H,d,J=15 Hz), 4.54-4.72 (1H,m), 5.09 (1H,d,J=15 Hz),5.3-5.6 (1H,br), 6.73-6.83 (2H,m), 7.31 (2H,d,J=9 Hz), 7.35-7.45 (1H,m),7.52 (2H,d,J=9 Hz), 7.75 (1H, s), 7.86 (1H,s).

Elemental Analysis for C₂₁ H₂₀ C₁ F₂ N₅ O₂ Calcd (%): C 56.32, H 4.50, N15.64 Found (%): C 56.35, H 4.36, N 15.93

IR (KBr) .sub.νmax : 3400, 1695, 1660, 1618, 1500, 1420, 1270 (cm⁻¹).

Working Example 11

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,5-piperazinedione(Compound 11) was obtained.

Colorless powder.

¹ H-NMR (CDCl₃) δ: 1.07(3H,d,J=7 Hz), 4.24-4.52 (6H,m), 4.74 (1H,d,J=18Hz), 5.16 (1H,d,J=14 Hz), 5.29 (1H,s), 5.36 (1H,q,J=7 Hz), 6.06(1H,tt,J=53 Hz,5 Hz), 6.74-6.83 (2H,m), 7.00 (2H,d,J=9 Hz), 7.29(2H,d,J=9 Hz), 7.31-7.47 (1H,m), 7.80 (1H,s ), 7.82 (1H,s).

IR (KBr) .sub.νmax : 3410, 1660, 1610, 1505, 1450, 1315 (cm⁻¹).

Working Example 12

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,5-piperazinedione,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,5-peperazinedione(Compound 12) was obtained.

White powder.

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 4.25-4.38 (2H,m), 4.45 (2H,s),4.74 (1H,d,J=17 Hz), 5.15 (1H,d,J=14 Hz), 5.30-5.41 (2H,m), 5.92(1H,tt,J=53 Hz,3 Hz), 6.73-6.82 (2H,m), 7.28 (2H,d,J=9 Hz), 7.30-7.45(3H,m), 7.79 (1H,s), 7.82 (1H,s).

Elemental analysis for C₂₄ H₂₁ F₆ N₅ O₄ Calcd (%): C 51.71, H 3.80, N12.56 Found (%): C 51.54, H 3.79, N 12.56

Working Example 13

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedione,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedione(Compound 14) was obtained.

White powder

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 3.79-3.90 (2H,m), 4.04-4.27(2H,m), 4.36 (2H,t,J=12 Hz), 4.39 (1H,d,J=13 Hz), 5.24 (1H,d,J=13 Hz),5.27-5.40 (2H,m), 6.06 (1H,tt,J=53 Hz,5 Hz), 6.72-6.83 (2H,m), 6.98(2H,d,J=9 Hz), 7.31-7.44 (3H,m), 7.78 (1H,s), 7.82 (1H,s).

Elemental analysis for C₂₅ H₂₃ F₆ N₅ O₄ Calcd (%): C 52.54, H 4.06, N12.25 Found (%): C 52.34, H 4.12, N 12.10

Working Example 14

Starting from1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,3-piperazinedione,1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2,3-piperazinedione(Compound 15) was obtained.

Colorless powdery crystals

¹ H-NMR (CDCl₃) δ: 1.07 (3H,d,J=7 Hz), 3.78-3.98 (2H,m), 4.10-4.29(2H,m), 4.40 (1H,d,J=15 Hz), 5.25 (2H,d,J=15 Hz), 5.25-5.40 (2H,m), 5.93(1H, tt, J=53 Hz, 3 Hz), 6.73-6.84 (2H,m), 7.28 (2H,d,J=9 Hz), 7.30-7.42(1H,m), 7.44 (2H,d,J=9 Hz), 7.79 (1H,s), 7.82 (1H,s).

Elemental analysis for C₂₄ H₂₁ F₆ N₅ O₄.0.5H₂ O Calcd (%): C 50.89, H3.91, N 12.36 Found (%): C 51.13, H 4.07, N 12.45

mp 174°-175° C.

Working Example 15

(Method A)

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone(Compound 16) was obtained.

(Method B)

In the same manner as in Working Example 3, starting from1-[(1R,2S)-2,3-epoxy-2-(2-fluorophenyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone(Compound 16) was obtained.

Colorless needles.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.0 Hz), 3.68-4.05 (4H,m), 4.51(1H,d,J=14.4 Hz), 4.65-4.80 (1H,m), 5.15 (1H,d,J=14.4 Hz), 5.25 (1H,br),5.91 (1H,tt,J=53.2 Hz,3 Hz), 6.95-7.63 (8H,m), 7.74 (1H,s), 7.82 (1H,s).

Elemental analysis for C₂₃ H₂₂ F₅ N₅ O₃ Calcd (%): C 54.01, H 4.34, N13.69 Found (%): C 53.96, H 4.48, N 13.69

Working Example 16

(Method A)

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone(Compound 17) was obtained.

(Method B)

In the same manner as in Working Example 3, starting from1-[(1R,2S)-2,3-epoxy-2-(2-fluorophenyl)-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone,1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone(Compound 17) was obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.0 Hz), 3.66-4.05 (4H,m), 4.33(2H,tt,J=12 Hz,l.6 Hz), 4.52 (1H,d,J=14 Hz), 4.60-4.77 (1H,m), 5.13(1H,d,J=14 Hz), 5.35 (1H,br), 6.07 (1H,tt.J=53 Hz,5 Hz), 6.91-7.53(8H,m), 7.73 (1H,s), 7.83 (1H,s).

Elemental analysis for C₂₄ H₂₄ F₅ N₅ O₃ Calcd (%): C 54.86, H 4.60, N13.33 Found (%): C 54.66, H 4.57, N 13.26

Working Example 17

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone(Compound 18) was obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.2 Hz), 3.69-4.02 (4H,m), 4.42(1H,q,J=7.2 Hz), 4.48 (1H,d,J=14 Hz), 4.72 (1H,d,J=14 Hz), 5.22-5.39(1H,bs), 5.91 (1H,tt.J=2.4 Hz,53 Hz), 6.93-7.01 (2H,m), 7.20-7.34(4H,m), 7.58 (2H,d,J=9 Hz), 7.65 (1H,s), 7.80 (1H,s).

Elemental analysis for C₂₃ H₂₂ F₅ N₅ O₃ Calcd (%): C 54.01, H 4.34, N13.69 Found (%): C 53.82, H 4.32, N 13.66

Working Example 18

In the same manner as in Working Example 1, starting from1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone,1-[(1R,2R)-2-(4-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone(Compound 19) was obtained.

Colorless powdery crystals.

¹ H-NMR (CDCl₃) δ: 1.06 (3H,d,J=7.2 Hz), 3.70-3.93 (4H,m), 4.28-4.45(3H,m), 4.49 (1H,d,J=14 Hz), 4.72 (1H,d,J=14 Hz), 5.32-5.48 (1H,bs),6.07 (1H,tt,J=5 Hz,53 Hz), 6.93-7.00 (4H,m), 7.30-7.34 (2H,m), 7.50(2H,d,J=9 Hz), 7.66 (1H,s), 7.80 (1H,s).

Elemental analysis for C₂₄ H₂₄ F₅ N₅ O₃ Calcd (%): C 54.86, H 4.60, N13.33 Found (%): C 54.86, H 4.68, N 12.94

A preferred group of the compounds belonging to the compound (I) of thepresent invention is exemplified in Table 3 and in Table 4 though thepresent invention is not limited thereto.

                  TABLE 3                                                         ______________________________________                                         ##STR37##                                                                    cpd.                                                                          No.   X       A                                                               ______________________________________                                        1     2,4-F.sub.2                                                                            ##STR38##                                                      2     2,4-F.sub.2                                                                            ##STR39##                                                      3     2,4-F.sub.2                                                                            ##STR40##                                                      4     2,4-F.sub.2                                                                            ##STR41##                                                      5     2,4-F.sub.2                                                                            ##STR42##                                                      6     2,4-F.sub.2                                                                            ##STR43##                                                      7     2,4-F.sub.2                                                                            ##STR44##                                                      8     2,4-F.sub.2                                                                            ##STR45##                                                      9     2,4-F.sub.2                                                                            ##STR46##                                                      ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        cpd.                                                                          No.   X       A                                                               ______________________________________                                        10    2,4-F.sub.2                                                                            ##STR47##                                                      11    2,4-F.sub.2                                                                            ##STR48##                                                      12    2,4-F.sub.2                                                                            ##STR49##                                                      13    2,4-F.sub.2                                                                            ##STR50##                                                      14    2,4-F.sub.2                                                                            ##STR51##                                                      15    2,4-F.sub.2                                                                            ##STR52##                                                      16    2-F                                                                                    ##STR53##                                                      17    2-F                                                                                    ##STR54##                                                      18    4-F                                                                                    ##STR55##                                                      19    4-F                                                                                    ##STR56##                                                      ______________________________________                                    

Preparation 1

Using the Compound 7 obtained in Working Example 7, the componentsstated below were mixed. The mixture was packed in gelatin capsules toobtain capsules, each of which contains the Compound 7 in an amount of50 mg.

    ______________________________________                                        Compound 7 (obtained in Working Example 7)                                                               50     mg                                          Lactose                    100    mg                                          Cornstarch                 40     mg                                          Magnesium stearate         10     mg                                          Total                      200    mg                                          ______________________________________                                    

Preparation 2

The Compound 4 obtained in Working Example 4 and magnesium stearate weregranulated in an aqueous solution of soluble starch. The resultingproduct was dried, and then mixed with lactose and cornstarch. Themixture was subjected to compression molding to obtain a tabletcontaining the components stated below.

    ______________________________________                                        Compound 4 (obtained in Working Example 4)                                                               50     mg                                          Lactose                    65     mg                                          Cornstarch                 30     mg                                          Soluble starch             35     mg                                          Magnesium stearate         20     mg                                          Total                      200    mg                                          ______________________________________                                    

Evaluation of the antifungal activities of the compound of the presentinvention was conducted by the following method: a sheet of filter paperdisc (manufactured by Toyo Seisakusho, 8 mm in diameter) soaked in a1000 μg/ml solution of a compound of the present invention in methanolwas placed on an agar plate containing various fungi, which wasincubated at 28° C. for two days, and the diameter of the growthinhibition zone around the filter paper disc was measured. The followingculture media were used: A: yeast nitrogen base agar medium (pH 7.0) B:peptone-yeast extract-glucose agar medium (pH 7.0)

The antifungal spectra of the compounds of the present invention areshown in Table 5.

                  TABLE 5                                                         ______________________________________                                                            Diameter of growth                                                            inhibition zone (mm)                                      Test microorganism                                                                             Medium   cpd.1   cpd.2                                                                              cpd.4                                  ______________________________________                                        Candida albicans A        36      45   41                                     IFO 0583                                                                      Candida utilis   A        25      29   31                                     IFO 0619                                                                      Aspergillus niger                                                                              A        24      27   26                                     IFO 4066                                                                      Aspergillus fumigatus                                                                          A        31      30   34                                     IFO 6344                                                                      Cryptococcus neoformans                                                                        A        27      31   29                                     IFO 0410                                                                      Trichophyton rubrum                                                                            B        47      50   43                                     IFO 5467                                                                      Trichophyton mentagrophytes                                                                    B        48      40   39                                     IFO 7522                                                                      Microsporum gypseum                                                                            B        49      41   42                                     IFO 6076                                                                      ______________________________________                                    

The antifungal activities of the compound of the present inventionagainst Candida albicans are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                 Diameter of growth-inhibition zone (mm)                                       Candida albicans IFO 0583                                            cpd. No. (Medium A. 28° C., two-day culture)                           ______________________________________                                        3        41                                                                   5        47                                                                   6        36                                                                   7        35                                                                   8        28                                                                   9        41                                                                   10       42                                                                   11       31                                                                   ______________________________________                                    

The protective effects of the compound of the present invention againstthe experimental infection in mice are shown in the following Tables 7and 8.

Test Method: Five-week-old Crj:CDF₁ mice were inoculated with theminimum lethal dose of Candida albicans TA intravenously. The testcompound was suspended in a solution of 0.2% or 0.5% sodiumcarboxymethylcellulose (CMC). The suspension was administered orallyonce immediately after infection. The activity was expressed in terms ofED₅₀ values calculated by the Reed and Muench method from the survivalrate 7 days after infection.

                  TABLE 7                                                         ______________________________________                                        cpd. No.  ED.sub.50 (mg/kg) P.O. [0.2% CMC]                                   ______________________________________                                        1         1.4                                                                 3         2.0                                                                 4         0.65                                                                7         0.65                                                                8         2.0                                                                 9         0.65                                                                10        1.8                                                                 ______________________________________                                         P.O. oral administration                                                 

                  TABLE 8                                                         ______________________________________                                        cpd. No.  ED.sub.50 (mg/kg) P.O. [0.5% CMC]                                   ______________________________________                                         6        0.71                                                                 7        0.35                                                                12        2.8                                                                 14        2.8                                                                 15        2.0                                                                 16        0.35                                                                17        0.65                                                                18        0.35                                                                19        0.77                                                                ______________________________________                                    

The protective effects of the compound of formula (VI), which is astarting compound of the present invention, against the experimentalinfection in mice are shown in the following Table 9.

Test Method: Five-week-old Crj:CDF₁ mice were inoculated with theminimum lethal dose of Candida albicans TA intravenously. The testcompound was suspended in a solution of 0.5% sodiumcarboxymethylcellulose (CMC). The suspension was administered orallyonce immediately after infection. The activity was expressed in terms ofED₅₀ values calculated by the Reed and Muench method from the survivalrate 7 days after infection.

                                      TABLE 9                                     __________________________________________________________________________     ##STR57##                                                                    Ref. Ex. No.                                                                         X  A'                     ED.sub.50 (mg/kg) P.O.                       __________________________________________________________________________    45     4-F                                                                               ##STR58##             0.18                                         46     4-F                                                                               ##STR59##             0.32                                         49     2-F                                                                               ##STR60##             0.18                                         50     2-F                                                                               ##STR61##             0.32                                         __________________________________________________________________________

The compound of the present invention or a salt thereof exhibitsexcellent antifungal activities. The compound of the present inventionor a salt thereof is useful for prevention and therapy of infections ofmammals as an antifungal agent. In addition, the compound of the presentinvention can be also used as an antifungal agent for agricultural use.

What we claimed is:
 1. A compound represented by the formula (I):##STR62## wherein Ar is an optionally-substituted phenyl group; R¹ andR² are, the same or different, a hydrogen atom or a lower alkyl group,or R¹ and R² may combine together to form a lower alkylene group; R³ isa hydrogen atom or an acyl group; Y is a nitrogen atom or a methinegroup; and R⁴ is a substituted phenyl group, or a salt thereof.
 2. Acompound of claim 1 in which one of R¹ and R² is a hydrogen atom andanother is a lower alkyl group.
 3. A compound of claim 1 in which Y is anitrogen atom.
 4. A compound of claim 1 in which Ar is ahalogen-substituted phenyl group.
 5. A compound of claim 4 in which Aris a phenyl group substituted with 1 or 2 fluorine atoms.
 6. A compoundof claim 1 in which R⁴ is a substituted phenyl group having 1 or 2substituents selected from the group consisting of a halogen atom, ahalogenated C₁₋₆ alkyl group and a halogenated C₁₋₆ alkoxy group.
 7. Acompound of claim 6 in which the substituent of the substituted phenylgroup is a fluorine atom, a fluorinated lower alkyl group or afluorinated lower alkoxy group.
 8. A compound of claim 1, which is1-[(1R,2R)]-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone.9. A compound of claim 1, which is1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone.10. A compound of claim 1, which is1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone.11. A compound of claim 1, which is1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone.12. A method for preventing or treating a fungal infection whichcomprises administering a pharmacological effective amount of a compoundof the formula (I) as defined in claim 1 or its pharmaceuticallyacceptable salt, optionally together with a carrier or diluent, to amammal suffering from the fungal infection.